Publisher: Sage Publications   (Total: 1166 journals)

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Showing 1 - 200 of 1166 Journals sorted alphabetically
AADE in Practice     Hybrid Journal   (Followers: 6)
Abstracts in Anthropology     Full-text available via subscription   (Followers: 29)
Academic Pathology     Open Access   (Followers: 6)
Accounting History     Hybrid Journal   (Followers: 18, SJR: 0.527, CiteScore: 1)
Acta Radiologica     Hybrid Journal   (Followers: 1, SJR: 0.754, CiteScore: 2)
Acta Radiologica Open     Open Access   (Followers: 2)
Acta Sociologica     Hybrid Journal   (Followers: 39, SJR: 0.939, CiteScore: 2)
Action Research     Hybrid Journal   (Followers: 53, SJR: 0.308, CiteScore: 1)
Active Learning in Higher Education     Hybrid Journal   (Followers: 396, SJR: 1.397, CiteScore: 2)
Adaptive Behavior     Hybrid Journal   (Followers: 9, SJR: 0.288, CiteScore: 1)
Administration & Society     Hybrid Journal   (Followers: 18, SJR: 0.675, CiteScore: 1)
Adoption & Fostering     Hybrid Journal   (Followers: 25, SJR: 0.313, CiteScore: 0)
Adsorption Science & Technology     Open Access   (Followers: 9, SJR: 0.258, CiteScore: 1)
Adult Education Quarterly     Hybrid Journal   (Followers: 259, SJR: 0.566, CiteScore: 2)
Adult Learning     Hybrid Journal   (Followers: 51)
Advances in Dental Research     Hybrid Journal   (Followers: 11, SJR: 1.791, CiteScore: 4)
Advances in Developing Human Resources     Hybrid Journal   (Followers: 35, SJR: 0.614, CiteScore: 2)
Advances in Mechanical Engineering     Open Access   (Followers: 156, SJR: 0.272, CiteScore: 1)
Advances in Methods and Practices in Psychological Science     Full-text available via subscription   (Followers: 20)
Advances in Structural Engineering     Full-text available via subscription   (Followers: 51, SJR: 0.599, CiteScore: 1)
AERA Open     Open Access   (Followers: 14)
Affilia     Hybrid Journal   (Followers: 6, SJR: 0.496, CiteScore: 1)
Africa Spectrum     Open Access   (Followers: 17)
Agrarian South : J. of Political Economy     Hybrid Journal   (Followers: 3)
Air, Soil & Water Research     Open Access   (Followers: 13, SJR: 0.214, CiteScore: 1)
Alexandria : The J. of National and Intl. Library and Information Issues     Full-text available via subscription   (Followers: 68)
Allergy & Rhinology     Open Access   (Followers: 5)
AlterNative : An Intl. J. of Indigenous Peoples     Full-text available via subscription   (Followers: 39, SJR: 0.194, CiteScore: 0)
Alternative Law J.     Hybrid Journal   (Followers: 12, SJR: 0.176, CiteScore: 0)
Alternatives : Global, Local, Political     Hybrid Journal   (Followers: 12, SJR: 0.351, CiteScore: 1)
Alternatives to Laboratory Animals     Full-text available via subscription   (Followers: 11, SJR: 0.297, CiteScore: 1)
American Behavioral Scientist     Hybrid Journal   (Followers: 26, SJR: 0.982, CiteScore: 2)
American Economist     Hybrid Journal   (Followers: 7)
American Educational Research J.     Hybrid Journal   (Followers: 259, SJR: 2.913, CiteScore: 3)
American J. of Alzheimer's Disease and Other Dementias     Hybrid Journal   (Followers: 23, SJR: 0.67, CiteScore: 2)
American J. of Cosmetic Surgery     Hybrid Journal   (Followers: 9)
American J. of Evaluation     Hybrid Journal   (Followers: 18, SJR: 0.646, CiteScore: 2)
American J. of Health Promotion     Hybrid Journal   (Followers: 35, SJR: 0.807, CiteScore: 1)
American J. of Hospice and Palliative Medicine     Hybrid Journal   (Followers: 47, SJR: 0.65, CiteScore: 1)
American J. of Law & Medicine     Full-text available via subscription   (Followers: 12, SJR: 0.204, CiteScore: 1)
American J. of Lifestyle Medicine     Hybrid Journal   (Followers: 7, SJR: 0.431, CiteScore: 1)
American J. of Medical Quality     Hybrid Journal   (Followers: 13, SJR: 0.777, CiteScore: 1)
American J. of Men's Health     Open Access   (Followers: 9, SJR: 0.595, CiteScore: 2)
American J. of Rhinology and Allergy     Hybrid Journal   (Followers: 11, SJR: 0.972, CiteScore: 2)
American J. of Sports Medicine     Hybrid Journal   (Followers: 247, SJR: 3.949, CiteScore: 6)
American Politics Research     Hybrid Journal   (Followers: 36, SJR: 1.313, CiteScore: 1)
American Review of Public Administration     Hybrid Journal   (Followers: 28, SJR: 2.062, CiteScore: 2)
American Sociological Review     Hybrid Journal   (Followers: 356, SJR: 6.333, CiteScore: 6)
American String Teacher     Full-text available via subscription   (Followers: 3)
Analytical Chemistry Insights     Open Access   (Followers: 26, SJR: 0.224, CiteScore: 1)
Angiology     Hybrid Journal   (Followers: 5, SJR: 0.849, CiteScore: 2)
Animation     Hybrid Journal   (Followers: 15, SJR: 0.197, CiteScore: 0)
Annals of Clinical Biochemistry     Hybrid Journal   (Followers: 10, SJR: 0.634, CiteScore: 1)
Annals of Otology, Rhinology & Laryngology     Hybrid Journal   (Followers: 20, SJR: 0.807, CiteScore: 1)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 58, SJR: 1.096, CiteScore: 2)
Annals of the American Academy of Political and Social Science     Hybrid Journal   (Followers: 51, SJR: 1.225, CiteScore: 3)
Annals of the ICRP     Hybrid Journal   (Followers: 4, SJR: 0.548, CiteScore: 1)
Anthropocene Review     Hybrid Journal   (Followers: 8, SJR: 3.341, CiteScore: 7)
Anthropological Theory     Hybrid Journal   (Followers: 48, SJR: 0.739, CiteScore: 1)
Antitrust Bulletin     Hybrid Journal   (Followers: 14)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2, SJR: 0.635, CiteScore: 2)
Antyajaa : Indian J. of Women and Social Change     Hybrid Journal   (Followers: 1)
Applied Biosafety     Hybrid Journal   (Followers: 1, SJR: 0.131, CiteScore: 0)
Applied Psychological Measurement     Hybrid Journal   (Followers: 21, SJR: 1.17, CiteScore: 1)
Applied Spectroscopy     Full-text available via subscription   (Followers: 27, SJR: 0.489, CiteScore: 2)
Armed Forces & Society     Hybrid Journal   (Followers: 25, SJR: 0.29, CiteScore: 1)
Arthaniti : J. of Economic Theory and Practice     Full-text available via subscription  
Arts and Humanities in Higher Education     Hybrid Journal   (Followers: 49, SJR: 0.305, CiteScore: 1)
Asia Pacific Media Educator     Hybrid Journal   (Followers: 1, SJR: 0.23, CiteScore: 0)
Asia-Pacific J. of Management Research and Innovation     Full-text available via subscription   (Followers: 3)
Asia-Pacific J. of Public Health     Hybrid Journal   (Followers: 15, SJR: 0.558, CiteScore: 1)
Asia-Pacific J. of Rural Development     Hybrid Journal   (Followers: 2)
Asian and Pacific Migration J.     Full-text available via subscription   (Followers: 8, SJR: 0.324, CiteScore: 1)
Asian Cardiovascular and Thoracic Annals     Hybrid Journal   (Followers: 2, SJR: 0.305, CiteScore: 0)
Asian J. of Comparative Politics     Hybrid Journal   (Followers: 5)
Asian J. of Legal Education     Full-text available via subscription   (Followers: 4)
Asian J. of Management Cases     Hybrid Journal   (Followers: 6, SJR: 0.101, CiteScore: 0)
ASN Neuro     Open Access   (Followers: 2, SJR: 1.534, CiteScore: 3)
Assessment     Hybrid Journal   (Followers: 19, SJR: 1.519, CiteScore: 3)
Assessment for Effective Intervention     Hybrid Journal   (Followers: 15, SJR: 0.578, CiteScore: 1)
Australasian J. of Early Childhood     Hybrid Journal   (Followers: 7, SJR: 0.535, CiteScore: 1)
Australasian Psychiatry     Hybrid Journal   (Followers: 18, SJR: 0.433, CiteScore: 1)
Australian & New Zealand J. of Psychiatry     Hybrid Journal   (Followers: 30, SJR: 1.801, CiteScore: 2)
Australian and New Zealand J. of Criminology     Hybrid Journal   (Followers: 546, SJR: 0.612, CiteScore: 1)
Australian J. of Career Development     Hybrid Journal   (Followers: 5)
Australian J. of Education     Hybrid Journal   (Followers: 51, SJR: 0.403, CiteScore: 1)
Australian J. of Management     Hybrid Journal   (Followers: 13, SJR: 0.497, CiteScore: 1)
Autism     Hybrid Journal   (Followers: 356, SJR: 1.739, CiteScore: 4)
Autism & Developmental Language Impairments     Open Access   (Followers: 16)
Avian Biology Research     Hybrid Journal   (Followers: 6, SJR: 0.401, CiteScore: 1)
Behavior Modification     Hybrid Journal   (Followers: 14, SJR: 0.877, CiteScore: 2)
Behavioral and Cognitive Neuroscience Reviews     Hybrid Journal   (Followers: 27)
Behavioral Disorders     Hybrid Journal   (Followers: 1)
Beyond Behavior     Hybrid Journal   (Followers: 1)
Bible Translator     Hybrid Journal   (Followers: 13)
Biblical Theology Bulletin     Hybrid Journal   (Followers: 24, SJR: 0.184, CiteScore: 0)
Big Data & Society     Open Access   (Followers: 55)
Biochemistry Insights     Open Access   (Followers: 7)
Bioinformatics and Biology Insights     Open Access   (Followers: 12, SJR: 1.141, CiteScore: 2)
Biological Research for Nursing     Hybrid Journal   (Followers: 7, SJR: 0.685, CiteScore: 2)
Biomarker Insights     Open Access   (Followers: 1, SJR: 0.81, CiteScore: 2)
Biomarkers in Cancer     Open Access   (Followers: 11)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 13)
Biomedical Informatics Insights     Open Access   (Followers: 8)
Bioscope: South Asian Screen Studies     Hybrid Journal   (Followers: 4, SJR: 0.235, CiteScore: 0)
BMS: Bulletin of Sociological Methodology/Bulletin de Méthodologie Sociologique     Hybrid Journal   (Followers: 4, SJR: 0.226, CiteScore: 0)
Body & Society     Hybrid Journal   (Followers: 29, SJR: 1.531, CiteScore: 3)
Bone and Tissue Regeneration Insights     Open Access   (Followers: 2)
Brain and Neuroscience Advances     Open Access  
Brain Science Advances     Open Access  
Breast Cancer : Basic and Clinical Research     Open Access   (Followers: 12, SJR: 0.823, CiteScore: 2)
British J. of Music Therapy     Hybrid Journal   (Followers: 9)
British J. of Occupational Therapy     Hybrid Journal   (Followers: 252, SJR: 0.323, CiteScore: 1)
British J. of Pain     Hybrid Journal   (Followers: 31, SJR: 0.579, CiteScore: 2)
British J. of Politics and Intl. Relations     Hybrid Journal   (Followers: 39, SJR: 0.91, CiteScore: 2)
British J. of Visual Impairment     Hybrid Journal   (Followers: 14, SJR: 0.337, CiteScore: 1)
British J.ism Review     Hybrid Journal   (Followers: 18)
BRQ Business Review Quarterly     Open Access   (Followers: 1)
Building Acoustics     Hybrid Journal   (Followers: 4, SJR: 0.215, CiteScore: 1)
Building Services Engineering Research & Technology     Hybrid Journal   (Followers: 3, SJR: 0.583, CiteScore: 1)
Bulletin of Science, Technology & Society     Hybrid Journal   (Followers: 9)
Business & Society     Hybrid Journal   (Followers: 15)
Business and Professional Communication Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.348, CiteScore: 1)
Business Information Review     Hybrid Journal   (Followers: 17, SJR: 0.279, CiteScore: 0)
Business Perspectives and Research     Hybrid Journal   (Followers: 3)
Cahiers Élisabéthains     Hybrid Journal   (Followers: 1, SJR: 0.111, CiteScore: 0)
Calcutta Statistical Association Bulletin     Hybrid Journal   (Followers: 1)
California Management Review     Hybrid Journal   (Followers: 37, SJR: 2.209, CiteScore: 4)
Canadian Association of Radiologists J.     Full-text available via subscription   (Followers: 2, SJR: 0.463, CiteScore: 1)
Canadian J. of Kidney Health and Disease     Open Access   (Followers: 8, SJR: 1.007, CiteScore: 2)
Canadian J. of Nursing Research (CJNR)     Hybrid Journal   (Followers: 15)
Canadian J. of Occupational Therapy     Hybrid Journal   (Followers: 166, SJR: 0.626, CiteScore: 1)
Canadian J. of Psychiatry     Hybrid Journal   (Followers: 28, SJR: 1.769, CiteScore: 3)
Canadian J. of School Psychology     Hybrid Journal   (Followers: 12, SJR: 0.266, CiteScore: 1)
Canadian Pharmacists J. / Revue des Pharmaciens du Canada     Hybrid Journal   (Followers: 3, SJR: 0.536, CiteScore: 1)
Cancer Control     Open Access   (Followers: 2)
Cancer Growth and Metastasis     Open Access   (Followers: 1)
Cancer Informatics     Open Access   (Followers: 4, SJR: 0.64, CiteScore: 1)
Capital and Class     Hybrid Journal   (Followers: 10, SJR: 0.282, CiteScore: 1)
Cardiac Cath Lab Director     Full-text available via subscription   (Followers: 1)
Cardiovascular and Thoracic Open     Open Access   (Followers: 1)
Career Development and Transition for Exceptional Individuals     Hybrid Journal   (Followers: 10, SJR: 0.44, CiteScore: 1)
Cartilage     Hybrid Journal   (Followers: 6, SJR: 0.889, CiteScore: 3)
Cell Transplantation     Open Access   (Followers: 5, SJR: 1.023, CiteScore: 3)
Cephalalgia     Hybrid Journal   (Followers: 8, SJR: 1.581, CiteScore: 3)
Cephalalgia Reports     Open Access   (Followers: 4)
Child Language Teaching and Therapy     Hybrid Journal   (Followers: 34, SJR: 0.501, CiteScore: 1)
Child Maltreatment     Hybrid Journal   (Followers: 11, SJR: 1.22, CiteScore: 3)
Child Neurology Open     Open Access   (Followers: 6)
Childhood     Hybrid Journal   (Followers: 19, SJR: 0.894, CiteScore: 2)
Childhood Obesity and Nutrition     Open Access   (Followers: 12)
China Information     Hybrid Journal   (Followers: 9, SJR: 0.767, CiteScore: 2)
China Report     Hybrid Journal   (Followers: 11, SJR: 0.221, CiteScore: 0)
Chinese J. of Sociology     Full-text available via subscription   (Followers: 5)
Christian Education J. : Research on Educational Ministry     Hybrid Journal   (Followers: 1)
Chronic Illness     Hybrid Journal   (Followers: 6, SJR: 0.672, CiteScore: 2)
Chronic Respiratory Disease     Hybrid Journal   (Followers: 12, SJR: 0.808, CiteScore: 2)
Chronic Stress     Open Access  
Citizenship, Social and Economics Education     Full-text available via subscription   (Followers: 6, SJR: 0.145, CiteScore: 0)
Cleft Palate-Craniofacial J.     Hybrid Journal   (Followers: 8, SJR: 0.757, CiteScore: 1)
Clin-Alert     Hybrid Journal   (Followers: 1)
Clinical and Applied Thrombosis/Hemostasis     Open Access   (Followers: 32, SJR: 0.49, CiteScore: 1)
Clinical and Translational Neuroscience     Open Access   (Followers: 1)
Clinical Case Studies     Hybrid Journal   (Followers: 3, SJR: 0.364, CiteScore: 1)
Clinical Child Psychology and Psychiatry     Hybrid Journal   (Followers: 45, SJR: 0.73, CiteScore: 2)
Clinical EEG and Neuroscience     Hybrid Journal   (Followers: 8, SJR: 0.552, CiteScore: 2)
Clinical Ethics     Hybrid Journal   (Followers: 13, SJR: 0.296, CiteScore: 1)
Clinical Medicine Insights : Arthritis and Musculoskeletal Disorders     Open Access   (Followers: 3, SJR: 0.537, CiteScore: 2)
Clinical Medicine Insights : Blood Disorders     Open Access   (Followers: 1, SJR: 0.314, CiteScore: 2)
Clinical Medicine Insights : Cardiology     Open Access   (Followers: 8, SJR: 0.686, CiteScore: 2)
Clinical Medicine Insights : Case Reports     Open Access   (Followers: 1, SJR: 0.283, CiteScore: 1)
Clinical Medicine Insights : Circulatory, Respiratory and Pulmonary Medicine     Open Access   (Followers: 4, SJR: 0.425, CiteScore: 2)
Clinical Medicine Insights : Ear, Nose and Throat     Open Access   (Followers: 2)
Clinical Medicine Insights : Endocrinology and Diabetes     Open Access   (Followers: 33, SJR: 0.63, CiteScore: 2)
Clinical Medicine Insights : Oncology     Open Access   (Followers: 3, SJR: 1.129, CiteScore: 3)
Clinical Medicine Insights : Pediatrics     Open Access   (Followers: 3)
Clinical Medicine Insights : Psychiatry     Open Access   (Followers: 10)
Clinical Medicine Insights : Reproductive Health     Open Access   (Followers: 1, SJR: 0.776, CiteScore: 0)
Clinical Medicine Insights : Therapeutics     Open Access   (Followers: 1, SJR: 0.172, CiteScore: 0)
Clinical Medicine Insights : Trauma and Intensive Medicine     Open Access   (Followers: 4)
Clinical Medicine Insights : Urology     Open Access   (Followers: 3)
Clinical Medicine Insights : Women's Health     Open Access   (Followers: 4)
Clinical Nursing Research     Hybrid Journal   (Followers: 34, SJR: 0.471, CiteScore: 1)
Clinical Pathology     Open Access   (Followers: 5)
Clinical Pediatrics     Hybrid Journal   (Followers: 25, SJR: 0.487, CiteScore: 1)
Clinical Psychological Science     Hybrid Journal   (Followers: 16, SJR: 3.281, CiteScore: 5)
Clinical Rehabilitation     Hybrid Journal   (Followers: 78, SJR: 1.322, CiteScore: 3)
Clinical Risk     Hybrid Journal   (Followers: 5, SJR: 0.133, CiteScore: 0)
Clinical Trials     Hybrid Journal   (Followers: 22, SJR: 2.399, CiteScore: 2)
Clothing and Textiles Research J.     Hybrid Journal   (Followers: 28, SJR: 0.36, CiteScore: 1)
Collections : A J. for Museum and Archives Professionals     Full-text available via subscription   (Followers: 3)
Common Law World Review     Full-text available via subscription   (Followers: 17)
Communication & Sport     Hybrid Journal   (Followers: 8, SJR: 0.385, CiteScore: 1)
Communication and the Public     Hybrid Journal   (Followers: 2)
Communication Disorders Quarterly     Hybrid Journal   (Followers: 15, SJR: 0.458, CiteScore: 1)
Communication Research     Hybrid Journal   (Followers: 24, SJR: 2.171, CiteScore: 3)
Community College Review     Hybrid Journal   (Followers: 8, SJR: 1.451, CiteScore: 1)
Comparative Political Studies     Hybrid Journal   (Followers: 291, SJR: 3.772, CiteScore: 3)
Compensation & Benefits Review     Hybrid Journal   (Followers: 8)
Competition & Change     Hybrid Journal   (Followers: 12, SJR: 0.843, CiteScore: 2)

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Similar Journals
Journal Cover
Cell Transplantation
Journal Prestige (SJR): 1.023
Citation Impact (citeScore): 3
Number of Followers: 5  

  This is an Open Access Journal Open Access journal
ISSN (Print) 0963-6897 - ISSN (Online) 1555-3892
Published by Sage Publications Homepage  [1166 journals]
  • Stem Cells from Human Exfoliated Deciduous teeth Promote Hair Regeneration
           in Mouse

    • Authors: Xiaoshuang Zhang, Tong Lei, Peng Chen, Lei Wang, Jian Wang, Donghui Wang, Wenhuan Guo, Yabin Zhou, Quanhai Li, Hongwu Du
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Stem cells in different types may interact with each other to maintain homeostasis or growth and the interactions are complicated and extensive. There is increasing evidence that mesenchymal-epithelial interactions in early morphogenesis stages of both tooth and hair follicles show many similarities. In order to explore whether stem cells from one tissue could interact with cells from another tissue, a series of experiments were carried out. Here we successfully extracted and identified stem cells from human exfoliated deciduous teeth (SHED) of 8–12 years old kids, and then found that SHED could promote hair regeneration in a mouse model. In vitro, SHED shortened the hair regeneration cycle and promoted the proliferation and aggregation of dermal cells. In vivo, when SHED and skin cells of C57 mice were subcutaneously co-transplanted to nude mice, more hair was formed than skin cells without SHED. To further explore the molecular mechanism, epidermal and dermal cells were freshly extracted and co-cultured with SHED. Then several signaling molecules in hair follicle regeneration were detected and we found that the expression of Sonic Hedgehog (Shh) and Glioma-associated oncogene 1 (Gli1) was up-regulated. It seems that SHED may boost the prosperity of hairs by increase Shh/Gli1 pathway, which brings new perspectives in tissue engineering and damaged tissue repairing.
      Citation: Cell Transplantation
      PubDate: 2021-10-11T08:03:57Z
      DOI: 10.1177/09636897211042927
      Issue No: Vol. 30 (2021)
  • Mechanosensitive Non-Coding RNAs in Osteogenesis of Mesenchymal Stem Cells

    • Authors: Xiao Cen, Xuefeng Pan, Bo Zhang, Wei Huang, Xiner Xiong, Xinqi Huang, Jun Liu, Zhihe Zhao
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      In bone tissue engineering, tailored biomaterials mimicking mesenchymal stem cells (MSCs) niche could regulate cell behavior and fate decision. The mechanisms, however, remain obscure. Recently, increasing evidence has shown that non-coding RNAs (ncRNAs) are critical modulators of the mechano-induced MSCs’ responses. Mechanosensitive ncRNAs could convert various physical forces into biochemical signals, and orchestrate signaling networks that regulate the osteogenic differentiation of MSCs in their unique microenvironment. In this review, we focus on the mechanosensitive ncRNAs which could interpret mechanical stimuli during the osteogenesis of MSCs, summarize the signaling pathway networks by which these ncRNAs drive MSCs fate, and point out the limitations and the areas waiting for further exploration.
      Citation: Cell Transplantation
      PubDate: 2021-10-09T07:23:05Z
      DOI: 10.1177/09636897211051382
      Issue No: Vol. 30 (2021)
  • A Multiparametric Assessment of Human Islets Predicts Transplant Outcomes
           in Diabetic Mice

    • Authors: Hirotake Komatsu, Meirigeng Qi, Nelson Gonzalez, Mayra Salgado, Leonard Medrano, Jeffrey Rawson, Chris Orr, Keiko Omori, Jeffrey S. Isenberg, Fouad Kandeel, Yoko Mullen, Ismail H. Al-Abdullah
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Prior to transplantation into individuals with type 1 diabetes, in vitro assays are used to evaluate the quality, function and survival of isolated human islets. In addition to the assessments of these parameters in islet, they can be evaluated by multiparametric morphological scoring (0–10 points) and grading (A, B, C, D, and F) based on islet characteristics (shape, border, integrity, single cells, and diameter). However, correlation between the multiparametric assessment and transplantation outcome has not been fully elucidated. In this study, 55 human islet isolations were scored using this multiparametric assessment. The results were correlated with outcomes after transplantation into immunodeficient diabetic mice. In addition, the multiparametric assessment was compared with oxygen consumption rate of isolated islets as a potential prediction factor for successful transplantations. All islet batches were assessed and found to score: 9 points (n = 18, Grade A), 8 points (n = 19, Grade B), and 7 points (n = 18, Grade B). Islets that scored 9 (Grade A), scored 8 (Grade B) and scored 7 (Grade B) were transplanted into NOD/SCID mice and reversed diabetes in 81.2%, 59.4%, and 33.3% of animals, respectively (P < 0.0001). Islet scoring and grading correlated well with glycemic control post-transplantation (P < 0.0001) and reversal rate of diabetes (P < 0.05). Notably, islet scoring and grading showed stronger correlation with transplantation outcome compared to oxygen consumption rate. Taken together, a multiparametric assessment of isolated human islets was highly predictive of transplantation outcome in diabetic mice.
      Citation: Cell Transplantation
      PubDate: 2021-10-09T07:13:40Z
      DOI: 10.1177/09636897211052291
      Issue No: Vol. 30 (2021)
  • Hematopoietic Stem Cell Transplant for Sickle Cell Disease: PATIENT
           SELEction and Timing Based on Sickle Cell-Related Multiple Chronic

    • Authors: Tim Jang, George Mo, Connor Stewart, Leen Khoury, Natalie Ferguson, Ogechukwu Egini, John Muthu, Dibyendu Dutta, Moro Salifu, Seah H Lim
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Hematopoietic stem cell transplant (HSCT) is the only cure for patients with sickle cell disease (SCD). Although most SCD patients experience progressive end-organ damage and shortened lifespans, not all patients follow the same disease course, tempo, or outcome. Therefore, the dilemma facing physicians is weighing the selection of patients and timing for the procedure against donor type and transplant-related mortality and morbidity that go up with increasing age. On the other hand, the dilemma facing the patients and families is how acceptable HSCT that carries some mortality risks to them. We have analyzed the chronic conditions due to SCD in 449 patients to determine whether SCD-related multiple chronic conditions (MCC) can be risk-stratified to identify the group of patients predicted to not only have shortened lifespans but also functional limitation and poor quality of life so that these at-risk patients can be offered HSCT early and before MCC develops. We identified that the age of onset of the first SCD-related chronic conditions strongly predicted for the risks for disease-related MCC. SCD patients who suffered their first disease-related chronic condition before age 30 years developed MCC at a rate of 19.1 times faster than those at a later age. These patients are therefore high-risk patients and should be offered HSCT early in the course of their disease before multiple organ damage intervenes, even if matched-related donors are not available. This patient selection and timing approach provides a forum for an easy-to-understand and real-time discussion, including the choice of donor type, with SCD patients and families when considering HSCT.
      Citation: Cell Transplantation
      PubDate: 2021-10-09T07:11:50Z
      DOI: 10.1177/09636897211046559
      Issue No: Vol. 30 (2021)
  • Therapeutic and Systemic Adverse Events of Immune Checkpoint Inhibitors
           Targeting the PD-1/PD-L1 axis for Clinical Management of NSCLC

    • Authors: Jing Chen, Yaser Alduais, Baoan Chen
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Non-small-cell lung cancer takes up the majority of lung carcinoma-caused deaths. It is reported that targeting PD-1/PD-L1, a well-known immune evasion checkpoint, can eradicate tumor. Checkpoint inhibitors, such as monoclonal antibodies, are actively employed in cancer treatment. Thus, this review aimed to assess the therapeutic and toxic effects of PD-1/PD-L1 inhibitors in treatment of NSCLC. So far, 6 monoclonal antibodies blocking PD-1/PD-L1 interaction are identified and used in clinical trials and randomized controlled trials for NSCLC therapy. These antibody-based therapies for NSCLC were collected by using search engine PubMed, and articles about the assessment of adverse events were collected by using Google search. Route of administration and dosage are critical parameters for efficient immunotherapy. Although antibodies can improve overall survival and are expected to be target-specific, they can cause systemic adverse effects in the host. Targeting certain biomarkers can limit the toxicity of adverse effects of the antibody-mediated therapy. Clinical experts with knowledge of adverse effects (AEs) of checkpoint inhibitors can help manage and reduce mortalities associated with antibody-based therapy of NSCLC.
      Citation: Cell Transplantation
      PubDate: 2021-10-04T09:49:45Z
      DOI: 10.1177/09636897211041587
      Issue No: Vol. 30 (2021)
  • Improvement of Heart Function After Transplantation of Encapsulated Stem
           Cells Induced with miR-1/Myocd in Myocardial Infarction Model of Rat

    • Authors: Samaneh Khazaei, Masoud Soleimani, Seyed Hossein Ahmadi Tafti, Rouhollah Mehdinavaz Aghdam, Zohreh Hojati
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Cardiovascular disease is one of the most common causes of death worldwide. Mesenchymal stem cells (MSCs) are one of the most common sources in cell-based therapies in heart regeneration. There are several methods to differentiate MSCs into cardiac-like cells, such as gene induction. Moreover, using a three-dimensional (3D) culture, such as hydrogels increases efficiency of differentiation. In the current study, mouse adipose-derived MSCs were co-transduced with lentiviruses containing microRNA-1 (miR-1) and Myocardin (Myocd). Then, expression of cardiac markers, such as NK2 homeobox 5(Nkx2-5), GATA binding protein 4 (Gata4), and troponin T type 2 (Tnnt2) was investigated, at both gene and protein levels in two-dimensional (2D) culture and chitosan/collagen hydrogel (CS/CO) as a 3D culture. Additionally, after induction of myocardial infarction (MI) in rats, a patch containing the encapsulated induced cardiomyocytes (iCM/P) was implanted to MI zone. Subsequently, 30 days after MI induction, echocardiography, immunohistochemistry staining, and histological examination were performed to evaluate cardiac function. The results of quantitative real -time polymerase chain reaction (qRT-PCR) and immunocytochemistry showed that co-induction of miR-1 and Myocd in MSCs followed by 3D culture of transduced cells increased expression of cardiac markers. Besides, results of in vivo study implicated that heart function was improved in MI model of rats in iCM/P-treated group. The results suggested that miR-1/Myocd induction combined with encapsulation of transduced cells in CS/CO hydrogel increased efficiency of MSCs differentiation into iCMs and could improve heart function in MI model of rats after implantation.
      Citation: Cell Transplantation
      PubDate: 2021-10-04T09:47:52Z
      DOI: 10.1177/09636897211048786
      Issue No: Vol. 30 (2021)
  • CLPTM1L Is a Novel Putative Oncogene Promoting Tumorigenesis in Oral
           Squamous Cell Carcinoma

    • Authors: Yunwen Hou, Feifei Xue, Yu Fu, Guanying Feng, Ruixia Wang, Hua Yuan
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      This study aimed to explore the function of CLPTM1L in oral squamous cell carcinoma and mechanism of tumorigenesis. The expression of CLPTM1L was detected by immunohistochemistry. The localization in cells was detected by immunofluorescence. Cell invasion, proliferation, and migration were detected by transwell, CCK-8 and scratch-wound test. The possible characteristics of CLPTM1L were analysed in TCGA, GO, KEGG and String databases. IHC revealed that the expression of CLPTM1L in 92 cases of OSCC tissues was significantly higher (P < 0.01) than 29 cases of normal oral epithelium tissues. The expression of CLPTM1L was significantly higher in oral squamous cell carcinoma in TCGA database. CLPTM1L expression was not significantly correlated with the patients’ clinical parameters. High expression of CLPTM1L was associated with worse prognosis. Cox regression analysis demonstrated that the CLPTM1L expression was the significant risk factor. CLPTM1L was mainly localized in the perinuclear cytoplasm. The vitro studies revealed that the knockdown of CLPTM1L suppressed invasion, proliferation and migration. CLPTM1L related genes were enriched in protein processing in the endoplasmic reticulum, protein folding, endoplasmic reticulum formation, N-glycan biosynthesis, and protein hydroxylation. Highly expressed CLPTM1L may contribute to a poor prognosis and increase invasion, proliferation and migration of oral squamous cell carcinoma. CLPTM1L may play an important role in tumorgenesis and would be a valuable target gene for the treatment of oral squamous cell carcinoma.
      Citation: Cell Transplantation
      PubDate: 2021-09-29T06:27:17Z
      DOI: 10.1177/09636897211045970
      Issue No: Vol. 30 (2021)
  • Platelet-Derived Biomaterials Inhibit Nicotine-Induced Intervertebral Disc
           Degeneration Through Regulating IGF-1/AKT/IRS-1 Signaling Axis

    • Authors: Wen-Cheng Lo, Chi-Sheng Chiou, Feng-Chou Tsai, Chun-Hao Chan, Samantha Mao, Yue-Hua Deng, Chia-Yu Wu, Bou-Yue Peng, Win-Ping Deng
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Apart from aging process, adult intervertebral disc (IVD) undergoes various degenerative processes. However, the nicotine has not been well identified as a contributing etiology. According to a few studies, nicotine ingestion through smoking, air or clothing may significantly accumulate in active as well as passive smokers. Since nicotine has been demonstrated to adversely impact various physiological processes, such as sympathetic nervous system, leading to impaired vasculature and cellular apoptosis, we aimed to investigate whether nicotine could induce IVD degeneration. In particular, we evaluated dose-dependent impact of nicotine in vitro to simulate its chronic accumulation, which was later treated by platelet-derived biomaterials (PDB). Further, during in vivo studies, mice were subcutaneously administered with nicotine to examine IVD-associated pathologic changes. The results revealed that nicotine could significantly reduce chondrocytes and chondrogenic indicators (Sox, Col II and aggrecan). Mice with nicotine treatment also exhibited malformed IVD structure with decreased Col II as well as proteoglycans, which was significantly increased after PDB administration for 4 weeks. Mechanistically, PDB significantly restored the levels of IGF-1 signaling proteins, particularly pIGF-1 R, pAKT, and IRS-1, modulating ECM synthesis by chondrocytes. Conclusively, the PDB impart reparative and tissue regenerative processes by inhibiting nicotine-initiated IVD degeneration, through regulating IGF-1/AKT/IRS-1 signaling axis.
      Citation: Cell Transplantation
      PubDate: 2021-09-29T06:20:20Z
      DOI: 10.1177/09636897211045319
      Issue No: Vol. 30 (2021)
  • Benefit of Belatacept in Cord Blood-Derived Regulatory T Cell-Mediated
           Suppression of Alloimmune Response

    • Authors: Xing He, Sang Li, Juan Zhang, Lu Cao, Cejun Yang, Pengfei Rong, Shounan Yi, Kedar Ghimire, Xiaoqian Ma, Wei Wang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The role of Regulatory T cells (Tregs) in tolerance induction post-transplantation is well-established, but Tregs adoptive transfer alone without combined immunosuppressants have failed so far in achieving clinical outcomes. Here we applied a set of well-designed criteria to test the influence of commonly used immunosuppressants (belatacept, tacrolimus, and mycophenolate) on cord blood-derived Tregs (CB-Tregs). Our study shows that while none of these immunosuppressants modulated the stability and expression of homing molecules by CB-Tregs, belatacept met all other selective criteria, shown by its ability to enhance CB-Tregs-mediated in vitro suppression of the allogeneic response without affecting their viability, proliferation, mitochondrial metabolism and expression of functional markers. In contrast, treatment with tacrolimus or mycophenolate led to reduced expression of functional molecule GITR in CB-Tregs, impaired their viability, proliferation and mitochondrial metabolism. These findings indicate that belatacept could be considered as a candidate in Tregs-based clinical immunomodulation regimens to induce transplant tolerance.
      Citation: Cell Transplantation
      PubDate: 2021-09-27T08:32:38Z
      DOI: 10.1177/09636897211046556
      Issue No: Vol. 30 (2021)
  • Challenges in stem cell-derived islet replacement therapy can be overcome

    • Authors: Midhat H. Abdulreda, Per-Olof Berggren
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      In this Commentary, we echo the conclusions of a recent review titled “The promise of stem cell-derived islet replacement therapy,” which highlighted recent advances in producing glucose responsive “islets” from stem cells and the benefits of their use in islet transplant therapy in type 1 diabetes (T1D). The review also outlined the status of clinical islet transplantation and the challenges that have prevented it from reaching its full therapeutic promise. We agree with the conclusions of the review and suggest that the identified challenges may be overcome by using the eye anterior chamber as an islet transplant site. We anticipate that the combination of stem cell-derived islets and intraocular transplant could help this promising T1D therapy reach full fruition.
      Citation: Cell Transplantation
      PubDate: 2021-09-27T07:07:37Z
      DOI: 10.1177/09636897211045320
      Issue No: Vol. 30 (2021)
  • Retraction Notice

    • Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.

      Citation: Cell Transplantation
      PubDate: 2021-09-27T06:34:16Z
      DOI: 10.1177/09636897211031022
      Issue No: Vol. 30 (2021)
  • Mesenchymal Stem Cell-Induced Anti-Neuroinflammation Against Traumatic
           Brain Injury

    • Authors: Blaise Cozene, Nadia Sadanandan, Jeffrey Farooq, Chase Kingsbury, You Jeong Park, Zhen-Jie Wang, Alexa Moscatello, Madeline Saft, Justin Cho, Bella Gonzales-Portillo, Cesar V Borlongan
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Traumatic brain injury (TBI) is a pervasive and damaging form of acquired brain injury (ABI). Acute, subacute, and chronic cell death processes, as a result of TBI, contribute to the disease progression and exacerbate outcomes. Extended neuroinflammation can worsen secondary degradation of brain function and structure. Mesenchymal stem cell transplantation has surfaced as a viable approach as a TBI therapeutic due to its immunomodulatory and regenerative features. This article examines the role of inflammation and cell death in ABI as well as the effectiveness of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplants as a treatment for TBI. Furthermore, we analyze new studies featuring transplanted BM-MSCs as a neurorestorative and anti-inflammatory therapy for TBI patients. Although clinical trials support BM-MSC transplants as a viable TBI treatment due to their promising regenerative characteristics, further investigation is imperative to uncover innovative brain repair pathways associated with cell-based therapy as stand-alone or as combination treatments.
      Citation: Cell Transplantation
      PubDate: 2021-09-24T07:50:34Z
      DOI: 10.1177/09636897211035715
      Issue No: Vol. 30 (2021)
  • Comparative Bioactivity Analysis for Off-the-Shelf and Culture–Rescued
           Umbilical Cord-Derived Mesenchymal Stem/Stromal Cells in a Xeno- and
           Serum-Free Culture System

    • Authors: Minh Quang Nguyen, Hue T. H. Bui, Anh Nguyen Thi Tuyet, Trinh Thi Hong Nhung, Duc M. Hoang, Nguyen Thanh Liem, Van T. Hoang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      We recently reported a standardized xeno- and serum-free culture platform to isolate and expand umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs). Comparing populations from the same passage, cells that were cryopreserved and culture-rescued exhibited characteristics similar to those of their fresh counterparts, continuously cultured cells without interim cryopreservation. The culture rescue after thawing allowed for the cells to be fully recovered. However, since it would be more cost-effective and timesaving if cryopreserved cells can be used as an off-the-shelf product, we set out to compare the bioactivity of freshly thawed UC-MSCs versus culture-rescued UC-MSCs of the same batch that were recultured for an additional passage under our xeno- and serum-free protocol. UC-MSCs showed high viability in both the freshly thawed and the re-cultured group. Both populations displayed a similar proliferation capacity which is indicated by a comparable population doubling time and colony-forming ability. Both freshly thawed and culture-rescued UC-MSCs expressed the characteristic immunophenotype and were capable of differentiating into osteocytes, chondrocytes, and adipocytes. On the other hand, culture-rescued cells appeared to be more potent in immunosuppression than freshly thawed cells. In conclusion, freshly thawed and culture-rescued cell products share comparable bioactivity in cell growth and proliferation, immunophenotype, and differentiation potential. However, the culture-rescued cells that were allowed to grow for an additional passage appear to display a more favorable immunomodulatory potential when compared to their freshly thawed parent cells.
      Citation: Cell Transplantation
      PubDate: 2021-09-19T04:12:07Z
      DOI: 10.1177/09636897211039441
      Issue No: Vol. 30 (2021)
  • Impact of Injection Frequency of Adipose-Derived Stem Cells on Allogeneic
           Skin Graft Survival Outcomes in Mice

    • Authors: Ju Long Hu, Byung Jun Kim, Na Hee Yu, Sung Tack Kwon
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Previous studies indicated that mesenchymal stem cells (MSCs) exhibit immunomodulatory properties in composite tissue allotransplantation. However, due to the high immunogenicity of skin, although the single administration of MSCs improves survival of the skin allotransplant, immune rejection is still inevitable. The aim of our study was to evaluate whether multiple administrations of MSCs would improve immune tolerance in the allogeneic skin graft, compared to that with a single administration in a mouse model. After full-thickness skin allotransplantation on the backs of the mice, the recipient mice were infused with phosphate-buffered saline and isogenic 1.5 × 105/mL adipose-derived stem cells (ADSCs). ADSCs were transplanted into different mice according to the different injection frequencies such as single, once a week, and twice a week. Skin sections were taken on days 7 and 21 post-transplantation in all groups for gene expression and histological studies. ADSCs increased skin allograft survival compared to that in control mice (P < 0.05). Interleukin-6 and tumor necrosis factor-alpha messenger RNA levels were decreased, and the abundance of lymphocytes, based on immunohistochemistry, was also decreased in ADSC-infused mice (P < 0.05). However, among the different ADSC injection frequency groups, multiple ADSC infusion did not improve the survival rate and decreased proinflammatory cytokines and lymphocytes, compared to those with the single administration of ADSCs (P> 0.05). Conversely, the results with single administration were slightly better than those with multiple administrations. Our study demonstrated that ADSCs have the potential for immunomodulation in vivo. However, the results with multiple ADSC administration were not as good as those with single administration, which indicates the complexity of ADSCs in vivo and implying the need for adequate preclinical experimentation.
      Citation: Cell Transplantation
      PubDate: 2021-09-19T03:18:23Z
      DOI: 10.1177/09636897211041966
      Issue No: Vol. 30 (2021)
  • Preferable Transplant Site for Hepatocyte Transplantation in a Rat Model

    • Authors: Hiroyuki Ogasawara, Akiko Inagaki, Ibrahim Fathi, Takehiro Imura, Hiroki Yamana, Yoshikatsu Saitoh, Muneyuki Matsumura, Kengo Fukuoka, Shigehito Miyagi, Yasuhiro Nakamura, Kazuo Ohashi, Michiaki Unno, Takashi Kamei, Masafumi Goto
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Intraportal injection is regarded as the current standard procedure of hepatocyte transplantation (HTx). In islet transplantation, which shares many aspects with HTx, recent studies have clarified that instant blood-mediated inflammatory reaction (IBMIR), characterized by strong innate immune responses, can cause poor engraftment, so other transplant sites to avoid such a reaction have been established. Although IBMIR was reported to occur in HTx, few reports have evaluated alternative transplant sites for HTx. In this study, we sought to determine the optimum transplant site for HTx. Rat hepatocytes (1.0 × 107) were transplanted at the 9 transplant sites (intraportal (IPO), intrasplenic (IS), liver parenchyma, subcutaneous, intraperitoneal, renal subcapsular, muscle, inguinal subcutaneous white adipose tissue, and omentum) of analbuminemic rats. The serum albumin levels, immunohistochemical staining (albumin, TUNEL, and BrdU), and in vivo imaging of the grafts were evaluated. The serum albumin levels of the IPO group were significantly higher than those of the other groups (p < .0001). The BrdU-positive hepatocyte ratio of liver in the IS group (0.9% ± 0.2%) was comparable to that of the IPO group (0.9% ± 0.3%) and tended to be higher than that of the spleen in the IS group (0.5% ± 0.1%, p = .16). Considering the in vivo imaging evaluation and the influence of splenectomy, the graft function in the IS group may be almost entirely achieved by hepatocytes that have migrated to the liver. The present study clearly showed that the intraportal injection procedure is more efficient than other procedures for performing HTx
      Citation: Cell Transplantation
      PubDate: 2021-09-16T04:53:58Z
      DOI: 10.1177/09636897211040012
      Issue No: Vol. 30 (2021)
  • Cibinetide Protects Isolated Human Islets in a Stressful Environment and
           Improves Engraftment in the Perspective of Intra Portal Islet

    • Authors: Ming Yao, Anna Domogatskaya, Nils Ågren1, Masaaki Watanabe, Kazuaki Tokodai, Michael Brines, Anthony Cerami, Bo-Göran Ericzon, Makiko Kumagai-Braesch, Torbjörn Lundgren
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      During intra-portal pancreatic islet transplantation (PITx), innate immune reactions such as the instant blood mediated inflammatory reaction (IBMIR) cause an immediate loss of islets. The non-hematopoietic erythropoietin analogue cibinetide has previously shown islet-protective effects in mouse PITx. Herein, we aimed to confirm cibinetide’s efficacy on human islets, and to characterize its effect on IBMIR. We cultured human islets with pro-inflammatory cytokines for 18 hours with or without cibinetide. ATP content and caspase 3/7 activity were measured. Dynamic glucose perfusion assay was used to evaluate islet function. To evaluate cibinetides effect on IBMIR, human islets were incubated in heparinized polyvinyl chloride tubing system with ABO compatible blood and rotated for 60 minutes to mimic the portal vein system. Moreover, human islets were transplanted into athymic mice livers via the portal vein with or without perioperative cibinetide treatment. The mice were sacrificed six days following transplantation and the livers were analyzed for human insulin and serum for human C-peptide levels. Histological examination of recipient livers to evaluate islet graft infiltration by CD11b+ cells was performed. Our results show that cibinetide maintained human islet ATP levels and reduced the caspase 3/7 activity during culture with pro-inflammatory cytokines and improved their insulin secreting capacity. In the PVC loop system, administration of cibinetide reduced the IBMIR-induced platelet consumption. In human islet to athymic mice PITx, cibinetide treatment showed an increased amount of human insulin in the livers and higher serum human C-peptide, while histological examination of the livers showed reduced infiltration of pro-inflammatory CD11b+ cells around islets grafts compared to the controls. In summary, Cibinetide protected isolated human islets in a pro-inflammatory milieu and reduced IBMIR related platelet consumption. It improved engraftment of human islets in athymic mice. The study confirms that cibinetide is a promising agent to be used in clinical PITx.
      Citation: Cell Transplantation
      PubDate: 2021-09-09T11:55:08Z
      DOI: 10.1177/09636897211039739
      Issue No: Vol. 30 (2021)
  • Cell Transplantation to Restore Lost Auditory Nerve Function is a
           Realistic Clinical Opportunity

    • Authors: Tetsuji Sekiya, Matthew C. Holley
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Hearing is one of our most important means of communication. Disabling hearing loss (DHL) is a long-standing, unmet problem in medicine, and in many elderly people, it leads to social isolation, depression, and even dementia. Traditionally, major efforts to cure DHL have focused on hair cells (HCs). However, the auditory nerve is also important because it transmits electrical signals generated by HCs to the brainstem. Its function is critical for the success of cochlear implants as well as for future therapies for HC regeneration. Over the past two decades, cell transplantation has emerged as a promising therapeutic option for restoring lost auditory nerve function, and two independent studies on animal models show that cell transplantation can lead to functional recovery. In this article, we consider the approaches most likely to achieve success in the clinic. We conclude that the structure and biochemical integrity of the auditory nerve is critical and that it is important to preserve the remaining neural scaffold, and in particular the glial scar, for the functional integration of donor cells. To exploit the natural, autologous cell scaffold and to minimize the deleterious effects of surgery, donor cells can be placed relatively easily on the surface of the nerve endoscopically. In this context, the selection of donor cells is a critical issue. Nevertheless, there is now a very realistic possibility for clinical application of cell transplantation for several different types of hearing loss.
      Citation: Cell Transplantation
      PubDate: 2021-09-09T11:37:08Z
      DOI: 10.1177/09636897211035076
      Issue No: Vol. 30 (2021)
  • ASNTR Abstracts 2021

    • Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.

      Citation: Cell Transplantation
      PubDate: 2021-09-06T08:59:03Z
      DOI: 10.1177/09636897211033705
      Issue No: Vol. 30 (2021)
  • Delta Opioid Receptor Activation with Delta Opioid Peptide [d-Ala2,
           d-Leu5] Enkephalin Contributes to Synaptic Improvement in Rat Hippocampus
           against Global Ischemia

    • Authors: Guangming Zhang, Zelin Lai, Lingling Gu, Kejia Xu, Zhenlu Wang, Yale Duan, Huifen Chen, Min Zhang, Jun Zhang, Zheng Zhao, Shuyan Wang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Global cerebral ischemia induced by cardiac arrest usually leads to poor neurological outcomes. Numerous studies have focused on ways to prevent ischemic damage in the brain, however clinical therapies are still limited. Our previous studies revealed that delta opioid receptor (DOR) activation with [d-Ala2, d-Leu5] enkephalin (DADLE), a DOR agonist, not only significantly promotes neuronal survival on day 3, but also improves spatial memory deficits on days 5-9 after ischemia. However, the neurological mechanism underlying DADLE-induced cognitive recovery remains unclear. This study first examined the changes in neuronal survival in the CA1 region at the advanced time point (day 7) after ischemia/reperfusion (I/R) injury and found a significant amelioration of damaged CA1 neurons in the rats treated with DADLE (2.5 nmol) when administered at the onset of reperfusion. The structure and function of CA1 neurons on days 3 and 7 post-ischemia showed significant improvements in both the density of the injured dendritic spines and the basic transmission of the impaired CA3-CA1 synapses following DADLE treatment. The molecular changes involved in DADLE-mediated synaptic modulation on days 3 and 7 post-ischemia implied the time-related differential regulation of PKCα-MARCKS on the dendritic spine structure and of BDNF- ERK1/2-synapsin I on synaptic function, in response to ischemic/reperfusion injury as well as to DADLE treatment. Importantly, all the beneficial effects of DADLE on ischemia-induced cellular, synaptic, and molecular deficits were eliminated by the DOR inhibitor naltrindole (2.5 nmol). Taken together, this study suggested that DOR activation-induced protective signaling pathways of PKCα-MARCKS involved in the synaptic morphology and BDNF-ERK-synapsin I in synaptic transmission may be engaged in the cognitive recovery in rats suffering from advanced cerebral ischemia.
      Citation: Cell Transplantation
      PubDate: 2021-09-02T05:57:29Z
      DOI: 10.1177/09636897211041585
      Issue No: Vol. 30 (2021)
  • Intrathecal Transplantation of Autologous and Allogeneic Bone
           Marrow-Derived Mesenchymal Stem Cells in Dogs

    • Authors: Felipe Pérez Benavides, Giovana Boff Araujo Pinto, Marta Cristina Thomas Heckler, Diana Milena Rodríguez Hurtado, Livia Ramos Teixeira, Marina Mitie de Souza Monobe, Gisele Fabrino Machado, Guilherme Dias de Melo, Diego Noé Rodríguez-Sánchez, Fernanda da Cruz Landim e Alvarenga, Rogério Martins Amorim
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The route used in the transplantation of mesenchymal stem cells (MSCs) can directly affect the treatment success. The transplantation of MSCs via the intrathecal (IT) route can be an important therapeutic strategy for neurological disorders. The objective of this study was to evaluate the safety and feasibility of the IT transplantation of autologous (Auto-MSCs) and allogeneic (Allo-MSCs) bone marrow mesenchymal stem cells (BM-MSCs) in healthy dogs. Based on neurodisability score, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI), no significant differences from the control group were observed on day 1 or day 5 after IT Auto- or Allo-MSCs transplantation (P> 0.05). In addition, analysis of matrix metalloproteinase (MMP)-2 and MMP-9 expression in the CSF revealed no significant differences (P> 0.05) at 5 days after IT transplantation in the Auto- or Allo-MSCs group when compared to the control. Intrathecal transplantation of BM-MSCs in dogs provides a safe, easy and minimally invasive route for the use of cell-based therapeutics in central nervous system diseases.
      Citation: Cell Transplantation
      PubDate: 2021-08-24T03:24:41Z
      DOI: 10.1177/09636897211034464
      Issue No: Vol. 30 (2021)
  • CTRP13 Protects H9c2 Cells Against Hypoxia/Reoxygenation (H/R)-Induced
           Injury Via Regulating the AMPK/Nrf2/ARE Signaling Pathway

    • Authors: Weifeng Jiang, Jungang Song, Suitao Zhang, Yanyan Ye, Jun Wang, Yilin Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Myocardial infarction (MI) is identified as the myocardial necrosis due to myocardial ischemia/reperfusion (I/R) injury and remains a leading cause of mortality. C1q/TNF-related protein 13 (CTRP13) is a member of CTRP family that has been found to be involved in coronary artery disease (CAD). However, the role of CTRP13 in MI remains unclear. We aimed to explore the functional role of CTRP13 in H9c2 cells exposed to hypoxia/reoxygenation (H/R). Our results demonstrated that H/R stimulation significantly decreased the expression of CTRP13 in H9c2 cells. H/R-induced an increase in ROS production and reductions in activities of SOD and CAT were prevented by CTRP13 overexpression but were aggravated by CTRP13 silencing. Moreover, CTRP13 overexpression could reverse the inductive effect of H/R on caspase-3 activity and bax expression, as well as the inhibitory effect of H/R on bcl-2 expression in H9c2 cells. However, CTRP13 silencing presented opposite effects with CTRP13 overexpression. Furthermore, CTRP13 overexpression enhanced the H/R-stimulated the expression levels of p-AMPK and nuclear Nrf2, and Nrf2 transcriptional activity. However, inhibition of AMPK reversed the CTRP13-mediated activation of Nrf2/ARE signaling and the cardiac-protective effect in H/R-exposed H9c2 cells. Additionally, silencing of Nrf2 reversed the protective effects of CTRP13 against H/R-stimulated oxidative stress and apoptosis in H9c2 cells. Finally, recombinant CTRP13 protein attenuated myocardial I/R-induced injury in rats. Taken together, these findings indicated that CTRP13 protected H9c2 cells from H/R-stimulated oxidative stress and apoptosis via regulating the AMPK/Nrf2/ARE signaling pathway. Our results provided evidence for the therapeutic potential of CTRP13 in myocardial I/R injury.
      Citation: Cell Transplantation
      PubDate: 2021-08-02T02:02:52Z
      DOI: 10.1177/09636897211033275
      Issue No: Vol. 30 (2021)
  • Long-Term Cryopreservation Does Not Affect Quality of Peripheral Blood
           Stem Cell Grafts: A Comparative Study of Native, Short-Term and Long-Term
           Cryopreserved Haematopoietic Stem Cells

    • Authors: Daniel Lysak, Michaela Brychtová, Martin Leba, Miroslava Čedíková, Daniel Georgiev, Pavel Jindra, Tomáš Vlas, Monika Holubova
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Cryopreserved haematopoietic progenitor cells are used to restore autologous haematopoiesis after high dose chemotherapy. Although the cells are routinely stored for a long period, concerns remain about the maximum storage time and the possible negative effect of storage on their potency. We evaluated the effect of cryopreservation on the quality of peripheral stem cell grafts stored for a short (3 months) and a long (10 years) period and we compared it to native products.The viability of CD34+ cells remained unaffected during storage, the apoptotic cells were represented up to 10% and did not differ between groups. The clonogenic activity measured by ATP production has decreased with the length of storage (ATP/cell 1.28 nM in native vs. 0.63 in long term stored products, P < 0.05). Only borderline changes without statistical significance were detected when examining mitochondrial and aldehyde dehydrogenase metabolic activity and intracellular pH, showing their good preservation during cell storage. Our experience demonstrates that cryostorage has no major negative effect on stem cell quality and potency, and therefore autologous stem cells can be stored safely for an extended period of at least 10 years. On the other hand, long term storage for 10 years and longer may lead to mild reduction of clonogenic capacity. When a sufficient dose of stem cells is infused, these changes will not have a clinical impact. However, in products stored beyond 10 years, especially when a low number of CD34+ cells is available, the quality of stem cell graft should be verified before infusion using the appropriate potency assays.
      Citation: Cell Transplantation
      PubDate: 2021-07-30T11:52:05Z
      DOI: 10.1177/09636897211036004
      Issue No: Vol. 30 (2021)
  • Stamina-Enhancing Effects of Human Adipose-Derived Stem Cells

    • Authors: Eun-Jung Yoon, Hye Rim Seong, Jangbeen Kyung, Dajeong Kim, Sangryong Park, Ehn-Kyoung Choi, Yun-Bae Kim, Dongsun Park
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Stamina-enhancing effects of human adipose derived stem cells (hADSCs) were investigated in young Sprague-Dawley rats. Ten-day-old male rats were transplanted intravenously (IV) or intracerebroventricularly (ICV) with hADSCs (1 × 106 cells/rat), and physical activity was measured by locomotor activity and rota-rod performance at post-natal day (PND) 14, 20, 30, and 40, as well as a forced swimming test at PND 41. hADSCs injection increased the moving time in locomotor activity, the latency in rota-rod performance, and the maximum swimming time. For the improvement of physical activity, ICV transplantation was superior to IV injection. In biochemical analyses, ICV transplantation of hADSCs markedly reduced serum creatine phosphokinase, lactate dehydrogenase, alanine transaminase, and muscular lipid peroxidation, the markers for muscular and hepatic injuries, despite the reduction in muscular glycogen and serum triglycerides as energy sources. Notably, hADSCs secreted brain-derived neurotrophic factor (BDNF) and nerve growth factor in vitro, and increased the level of BDNF in the brain and muscles in vivo. The results indicate that hADSCs enhance physical activity including stamina not only by attenuating tissue injury, but also by strengthening the muscles via production of BDNF.
      Citation: Cell Transplantation
      PubDate: 2021-07-28T11:32:53Z
      DOI: 10.1177/09636897211035409
      Issue No: Vol. 30 (2021)
  • α-Mangostin Induces Apoptosis in Human Osteosarcoma Cells Through
           ROS-Mediated Endoplasmic Reticulum Stress via the WNT Pathway

    • Authors: Shengsen Yang, Fei Zhou, Yi Dong, Fei Ren
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      α-mangostin has been confirmed to promote the apoptosis of MG-63 cells, but its specific pro-apoptosis mechanism in osteosarcoma (OS) remains further investigation. Here, we demonstrated that α-mangostin restrained the viability of OS cells (143B and Saos-2), but had little effect on the growth of normal human osteoblast. α-mangostin increased OS cell apoptosis by activating the caspase-3/8 cascade. Besides, α-mangostin induced endoplasmic reticulum (ER) stress and restrained the Wnt/β-catenin pathway activity. 4PBA (an ER stress inhibitor) or LiCl (an effective Wnt activator) treatment effectively hindered α-mangostin-induced apoptosis and the caspase-3/8 cascade. Furthermore, we also found that α-mangostin induced ER stress by promoting ROS production. And ER stress-mediated apoptosis caused by ROS accumulation depended on the inactivation of Wnt/β-catenin pathway. In addition, α-mangostin significantly hindered the growth of xenograft tumors, induced the expression of ER stress marker proteins and activation of the caspase-3/8 cascade, and restrained the Wnt/β-catenin signaling in vivo. In short, ROS-mediated ER stress was involved in α-mangostin triggered apoptosis, which might depended on Wnt/β-catenin signaling inactivation.
      Citation: Cell Transplantation
      PubDate: 2021-07-28T11:32:47Z
      DOI: 10.1177/09636897211035080
      Issue No: Vol. 30 (2021)
  • Effects of UCMSCs Delivered through Different Transplantation Approaches
           on Acute Radiation Enteritis in Rats

    • Authors: Jun Li, Yinghong Jiang, Hua Yu, Lejiang Liu, Qiang Wang, Hongpin Ju, Xuemei Zhang, Wenqi Wang, Xudong Yin, Qiong Wu, Jianzhong Xiao, Jianrong Miao, Xiao Ye, Tianyu Li, Hui Tian, Wei Xue
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Radiation enteritis is the most common and serious complication of abdominal or pelvic radiation therapy. Mesenchymal stem cells (MSCs), as well as cell protection agents, inhibit apoptosis and promote the proliferation of injured tissues. 3 human umbilical cords MSCs (UCMSCs) were injected into the tail vein or peritoneal cavity of a rat model of radiation enteritis. The temporary protective effect was assessed by identification of donor cells, detection of cellular immune parameters and inflammatory cytokine levels, quantitation of jejunum mucosal preservation and examination of the rat remaining life. Only the rats in the intraperitoneal injection group exhibited a few positive donor cells 7 days after transplantation. CD4 +/CD8 + T cells, a cellular immune parameter, decreased in the abdominal exudate of intraperitoneal injection group, compared with the model-only control and tail vein groups (both P < .05). Both serum and abdominal exudate TNF-α and IL-6 levels in the intraperitoneally injected rats rapidly decreased and were significantly different from those in the model-only control and tail vein injection groups (all P < .05). Mucosal surface area and survival time increased in the intraperitoneal injection group compared with the vehicle and tail vein injection groups (all P = .000). Therefore, the administration of UCMSCs with intraperitoneal injection approach postponed death in a rat model of radiation enteritis, which was associated with reduced serum levels of proinflammatory cytokines (TNF-α, IL-6). However, UCMSCs injected via the tail vein triggered an intense cellular immune response in the serum that adversely affects their survival. This treatment failed to suppress circulating serum and abdominal exudate levels of TNF-α and IL-6 and could not provide a therapeutic benefit for prolonging life against acute radiation enteritis.
      Citation: Cell Transplantation
      PubDate: 2021-07-28T11:32:26Z
      DOI: 10.1177/09636897211025230
      Issue No: Vol. 30 (2021)
  • Taxifolin Protects Dental Pulp Stem Cells under Hypoxia and Inflammation

    • Authors: Xiaohui Fu, Yimiao Feng, Bingyi Shao, Yanzhen Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Background:Dental pulp stem cells (DPSCs) are a unique source for future clinical application in dentistry such as periodontology or endodontics. However, DPSCs are prone to apoptosis under abnormal conditions. Taxifolin is a natural flavonoid and possesses many pharmacological activities including anti-hypoxic and anti-inflammatory. We aimed to elucidate the mechanisms of taxifolin protects DPSC under hypoxia and inflammatory conditions.Methods:DPSCs from human dental pulp tissue was purchased from Lonza (cat. no. PT-5025. Basel, Switzerland)) and identified by DPSC’s biomarkers. DPSC differentiation in vitro following the manufacturers’ instructions. ARS staining and Oil red staining verify the efficiency of differentiation in vitro after 2 weeks. The changes of various genes and proteins were identified by Q-PCR and western-blot, respectively. Cell viability was determined by the CCK-8 method, while apoptosis was determined by Annexin V/PI staining.Results:DPSC differentiation in vitro shows that hypoxia and TNF-α synergistically inhibit the survival and osteogenesis of DPSCs. A final concentration of 10 μM Taxifolin can significantly reduce the apoptosis of DPSCs under inflammation and hypoxia conditions. Taxifolin substantially increases carbonic anhydrase IX (CA9) expression but not HIF1a, and inhibitions of CA9 expression nullify the protective role of taxifolin under hypoxia and inflammatory condition.Conclusion:Taxifolin significantly increased the expression of CA9 when it inhibits DPSC apoptosis and taxifolin synergistically to protect DPSCs against apoptosis with CA9 under hypoxia and inflammatory conditions. Taxifolin can be used as a potential drug for clinical treatment of DPSC-related diseases.
      Citation: Cell Transplantation
      PubDate: 2021-07-22T01:54:59Z
      DOI: 10.1177/09636897211034452
      Issue No: Vol. 30 (2021)
  • Corrigendum

    • Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.

      Citation: Cell Transplantation
      PubDate: 2021-07-20T09:00:56Z
      DOI: 10.1177/09636897211027078
      Issue No: Vol. 30 (2021)
  • Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in
           Acute Graft-Versus-Host Disease

    • Authors: Xi Sun, Qiaomei He, Jun Yang, Andi Wang, Fang Zhang, Huiying Qiu, Kun Zhou, Pengran Wang, Xiaodan Ding, Xiujie Yuan, Huajun Li, Yan Zhang, Xianmin Song
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Acute graft-versus-host disease (aGVHD) is one of the most common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Janus kinase (JAK) inhibitors are considered as reliable and promising agents for patients with aGVHD. The prophylactic and therapeutic effects of SHR0302, a novel JAK inhibitor, were evaluated in aGVHD mouse models. The overall survival (OS), progression-free survival (PFS), bodyweight of mice, GVHD scores were observed and recorded. The bone marrow and spleen samples of diseased model mice or peripheral blood of patients were analyzed. SHR0302 could prevent and reverse aGVHD in mouse models with preserving graft-versus-tumor effect. Functionally, SHR0302 improved the OS and PFS, restored bodyweight, reduced GVHD scores, and reduced immune cells infiltrated in target tissues. SHR0302 treatment also enhanced the hematopoietic reconstruction compared to the control group. Mechanistically, our results suggested that SHR0302 could inhibit the activation of T cells and modulate the differentiation of helper T (Th) cells by reducing Th1 and increasing regulatory T (Treg) cells. In addition, SHR0302 decreased the expression of chemokine receptor CXCR3 on donor T cells and the secretion of cytokines or chemokines including interleukin (IL)-6, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), CXCL10, etc. thereby destroying the IFN-γ/CXCR3/CXCL10 axis which promotes the progression of GVHD. Besides, SHR0302 decreased the phosphorylation of JAK and its downstream STATs, AKT and ERK1/2, which ultimately regulated the activation, proliferation, and differentiation of lymphocytes. Experiments on primary cells from aGVHD patients also confirmed the results. In summary, our results indicated that JAK inhibitor SHR0302 might be used as a novel agent for patients with aGVHD.
      Citation: Cell Transplantation
      PubDate: 2021-07-16T09:17:42Z
      DOI: 10.1177/09636897211033778
      Issue No: Vol. 30 (2021)
  • Knockdown of LncRNA LINC00958 Inhibits the Proliferation and Migration of
           NSCLC Cells by MiR-204-3p/KIF2A Axis

    • Authors: Qing Wang, Kai Li, Xiaoliang Li
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence suggests that long non-coding RNAs (lncRNAs) function in the tumorigenesis of NSCLC. LINC00958, a newly identified lncRNA, has been reported to be closely linked to tumorigenesis in several cancers. However, its specific role in NSCLC remains unclear. In this study, we determined the expression of LINC00958 in NSCLC by RT-qPCR analysis and evaluated cell proliferation and migration by CCK-8 and transwell assays, respectively. We established a xenograft tumor model to examine the effect of LINC00958 on tumor growth in vivo. Luciferase reporter assays were performed to determine the interaction between LINC00958 and miR-204-3p and the interaction between miR-204-3p and KIF2A. We found that LINC00958 was up-regulated in NSCLC tissues and cell lines. Down-regulation of LINC00958 inhibited cell proliferation and migration in vitro and suppressed tumor growth in vivo. Besides, miR-204-3p was identified as a target of LINC00958 and miR-204-3p inhibitor could reverse the inhibitory effect of LINC00958 knockdown on proliferation and migration of NSCLC cells. We also validated that KIF2A, a direct target of miR-204-3p, was responsible for the biological role of LINC00958. KIF2A antagonized the effect of miR-204-3p on NSCLC cell proliferation and migration and was regulated by LINC00958/miR-204-3p. Taken together, these data indicate that the LINC00958/miR-204-3p/KIF2A axis is critical for NSCLC progression, which might provide a potential therapeutic target of NSCLC.
      Citation: Cell Transplantation
      PubDate: 2021-07-16T09:06:47Z
      DOI: 10.1177/09636897211025500
      Issue No: Vol. 30 (2021)
  • Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering
           Pyruvate Kinase M2 Isoform Mediated Warburg Effect

    • Authors: Zhen Li, Lina Yang, Shuai Zhang, Jiaqi Song, Huanran Sun, Changliang Shan, Dan Wang, Shuangping Liu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Energy metabolism programming is a hallmark of cancer, and serves as a potent target of cancer therapy. Valproic acid (VPA), a broad Class I histone deacetylases (HDACs) inhibitor, has been used as a therapeutic agent for cancer. However, the detail mechanism about the potential role of VPA on the Warburg effect in breast cancer remains unclear. In this study, we highlight that VPA significantly attenuates the Warburg effect by decreasing the expression of pyruvate kinase M2 isoform (PKM2), leading to inhibited cell proliferation and reduced colony formation in breast cancer MCF-7 and MDA-MB-231 cells. Mechanistically, Warburg effect suppression triggered by VPA was mediated by inactivation of ERK1/2 phosphorylation through reduced HDAC1 expression, resulting in suppressing breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating the Warburg effect which is essential for developing the effective approach in breast cancer therapy.
      Citation: Cell Transplantation
      PubDate: 2021-07-15T10:15:56Z
      DOI: 10.1177/09636897211027524
      Issue No: Vol. 30 (2021)
  • Long Non-Coding RNA TP53TG1 Upregulates SHCBP1 to Promote Retinoblastoma
           Progression by Sponging miR-33b

    • Authors: Hongyi Wang, Zhen Zhang, Yue Zhang, Shihai Liu, Li Li
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Long non-coding RNA (lncRNA) TP53 target 1 (TP53TG1) is known to be strongly associated with tumor and cancer progression. However, its expression profile, unique role, and regulatory pathways in retinoblastoma (RB) are not known. Here, we revealed a large expression of TP53TG1 in RB tissues and cell lines. Conversely, we showed marked suppression of cell proliferation, migration, and invasion in TP53TG1 knocked down RB cells. Mechanistically, we established that TP53TG1 directly interacted with microRNA (miR)-33b in RB cells. Furthermore, TP53TG1 transcripts were found to be inversely correlated with miR-33b in RB tissues. We also showed that miR-33b suppression partly reversed the TP53TG1 knockdown mediated effects on tumor biology. Finally, TP53TG1 was shown to modulate the levels of SHC Binding and Spindle Associated 1 (SHCBP1), a direct target of miR-33b in RB cells. Based on the above data, we propose that TP53TG1 regulates RB progression via its modulation of the miR-33b/SHCBP1 pathway.
      Citation: Cell Transplantation
      PubDate: 2021-07-12T08:42:00Z
      DOI: 10.1177/09636897211025223
      Issue No: Vol. 30 (2021)
  • Metformin Antagonizes Ovarian Cancer Cells Malignancy Through MSLN
           Mediated IL-6/STAT3 Signaling

    • Authors: Xu Yang, Mei Huang, Qin Zhang, Jiao Chen, Juan Li, Qian Han, Lu Zhang, JiaQi Li, Shuai Liu, YuLan Ma, Lan Li, Lei Yang, SiYing Zou, Bin Han
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Background:Ovarian cancer is the most lethal gynecological malignancy, and chemotherapy remains the cornerstone for ovarian cancer management. Due to the unsatisfactory prognosis, a better understanding of the underlying molecular carcinogenesis is urgently required.Methods:Assays for determining cell growth, cell motility, and apoptosis were employed to evaluate the potential antitumor effects of metformin against ovarian cancer cells. Molecular biological methods were employed to explore the underlying mechanism. Human ovarian cancer samples and Gene Expression Profiling Interactive Analysis (GEPIA) dataset were used for uncovering the clinical significances of mesothelin (MSLN) on ovarian cancer.Results:In the present work, we found that metformin treatment led to cell growth and cell migration inhibition, and induced cell apoptosis. Metformin administration also impaired cancer cell stemness and the capillary-like structure formation capacity of SKOV3 cells. On mechanism, metformin treatment remarkably reduced mesothelin (MSLN) expression, downregulated IL-6/STAT3 signaling activity, subsequently resulted in VEGF and TGFβ1 expression. We also observed an oncogenic function of MSLN on ovarian cancer.Conclusions:Collectively, our findings suggested that metformin exerts anticancer effects by suppressing ovarian cancer cell malignancy, which attributed to MSLN inhibition mediated IL6/STAT3 signaling and VEGF and TGFβ1 downregulation.
      Citation: Cell Transplantation
      PubDate: 2021-07-09T08:40:54Z
      DOI: 10.1177/09636897211027819
      Issue No: Vol. 30 (2021)
  • The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical
           COVID-19 Patients: A Prospective Double Controlled Trial

    • Authors: G Adas, Z Cukurova, K Kart Yasar, R Yilmaz, N Isiksacan, P Kasapoglu, Z Yesilbag, ID Koyuncu, E Karaoz
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.
      Citation: Cell Transplantation
      PubDate: 2021-06-28T02:53:43Z
      DOI: 10.1177/09636897211024942
      Issue No: Vol. 30 (2021)
  • Label-Free Quantitative Proteome Profiling of Cerebrospinal Fluid from a
           Rat Stroke Model with Stem Cell Therapy

    • Authors: Junseok W Hur, Min-Sik Kim, Se-Yeon Oh, Ho-Young Kang, Jingi Bae, Hokeun Kim, Hangyeore Lee, Sang-Won Lee, Dong-Hyuk Park
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Human adipose-derived mesenchymal stem cells (hAMSCs) are capable of immunomodulation and regeneration after neural injury. For these reasons, hAMSCs have been investigated as a promising stem cell candidate for stroke treatment. However, noninvasive experiments studying the effects of grafted stem cells in the host brain have not yet been reported. Cerebrospinal fluid (CSF), which can be collected without sacrificing the subject, is involved in physiological control of the brain and reflects the pathophysiology of various neurological disorders of the central nervous system (CNS). Following stem cell transplantation in a stroke model, quantitative analysis of CSF proteome changes can potentially reveal the therapeutic effect of stem cells on the host CNS. We examined hAMSC-secreted proteins obtained from serum-free culture medium by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which identified several extracellular matrix proteins, supporting the well-known active paracrine function of hAMSCs. Subsequently, we performed label-free quantitative proteomic analysis on CSF samples from rat stroke models intravenously injected with hAMSC (experimental) or phosphate buffered saline (control). In total, 524 proteins were identified; among them, 125 and 91 proteins were increased and decreased with hAMSC treatment, respectively. Furthermore, gene set enrichment analysis revealed three proteins, 14-3-3 theta, MAG, and neurocan, that showed significant increases in the hAMSC-treated model; these proteins are core members of neurotrophin signaling, nerve growth factor (NGF) signaling, and glycosaminoglycan metabolism, respectively. Subsequent histological and neurologic function experiments validated proliferative neurogenesis in the hAMSC-treated stroke model. We conclude that (i) intravenous injection of hAMSCs can induce neurologic recovery in a rat stroke model and (ii) CSF may reflect the therapeutic effect of hAMSCs. Additionally, proteins as 14-3-3 theta, MAG, and neurocan could be considered as potential CSF biomarkers of neuroregeneration. These CSF proteome profiling results would be utilized as valuable resource in further stroke studies.
      Citation: Cell Transplantation
      PubDate: 2021-06-27T11:57:18Z
      DOI: 10.1177/09636897211023474
      Issue No: Vol. 30 (2021)
  • Incidence and Risk Factors Associated with Infection after Chimeric
           Antigen Receptor T Cell Therapy for Relapsed/Refractory B-cell

    • Authors: Feng Zhu, Guoqing Wei, Yandan Liu, Houli Zhou, Wenjun Wu, Luxin Yang, He Huang, Yongxian Hu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Chimeric antigen receptor T cells (CAR-Ts) constitute a novel therapeutic strategy for relapsed/refractory B-cell malignancies. With the extensive application of CAR-T therapy in clinical settings, CAR-T-associated toxicities have become increasingly apparent. However, information regarding the associated infections is limited. We aimed to evaluate the incidence of infection during CAR-T therapy and identify the potential risk factors. Especially, we evaluated infections and the associated risk factors in 92 patients. The cohort included patients with acute lymphoblastic leukemia (n = 58) and non-Hodgkin lymphoma (n = 34). Fifteen cases of infection (predominantly bacterial) were observed within 28 days of CAR-T therapy, with an infection density of 0.5 infections for every 100 days-at-risk. Neutropenia before CAR-T therapy (P = .005) and prior infection (P = .046) were independent risk factors associated with infection within 28 days after CAR-T therapy; corticosteroid treatment during cytokine release syndrome (P = .013) was an independent risk factor during days 29–180 after CAR-T infusions. Moreover, the 2-year survival duration was significantly shorter in patients with infections than in those without (126 vs 409 days; P = .006). Our results suggested that effective anti-infection therapies may improve prognosis of patients who have a high infection risk. The risk of bacterial infections during the early stages of CAR-T therapy and the subsequent risk of viral infections thereafter should be considered to provide the appropriate treatment and improve patient prognosis.
      Citation: Cell Transplantation
      PubDate: 2021-06-19T03:56:06Z
      DOI: 10.1177/09636897211025503
      Issue No: Vol. 30 (2021)
  • Intravenous Administration of Human Amniotic Mesenchymal Stem Cells in the
           Subacute Phase of Cerebral Infarction in a Mouse Model Ameliorates
           Neurological Disturbance by Suppressing Blood Brain Barrier Disruption and
           Apoptosis via Immunomodulation

    • Authors: Yasunori Yoshida, Toshinori Takagi, Yoji Kuramoto, Kotaro Tatebayashi, Manabu Shirakawa, Kenichi Yamahara, Nobutaka Doe, Shinichi Yoshimura
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Neuro-inflammation plays a key role in the pathophysiology of brain infarction. Cell therapy offers a novel therapeutic option due to its effect on immunomodulatory effects. Amniotic stem cells, in particular, show promise owing to their low immunogenicity, tumorigenicity, and easy availability from amniotic membranes discarded following birth. We have successfully isolated and expanded human amniotic mesenchymal stem cells (hAMSCs). Herein, we evaluated the therapeutic effect of hAMSCs on neurological deficits after brain infarction as well as their immunomodulatory effects in a mouse model in order to understand their mechanisms of action. One day after permanent occlusion of the middle cerebral artery (MCAO), hAMSCs were intravenously administered. RT-qPCR for TNFα, iNOS, MMP2, and MMP9, immunofluorescence staining for iNOS and CD11b/c, and a TUNEL assay were performed 8 days following MCAO. An Evans Blue assay and behavioral tests were performed 2 days and several months following MCAO, respectively. The results suggest that the neurological deficits caused by cerebral infarction are improved in dose-dependent manner by the administration of hAMSCs. The mechanism appears to be through a reduction in disruption of the blood brain barrier and apoptosis in the peri-infarct region through the suppression of pro-inflammatory cytokines and the M2-to-M1 phenotype shift.
      Citation: Cell Transplantation
      PubDate: 2021-06-19T03:56:05Z
      DOI: 10.1177/09636897211024183
      Issue No: Vol. 30 (2021)
  • Stem Cell-Based Therapy for Asherman Syndrome: Promises and Challenges

    • Authors: Yiyin Gao, Guijie Wu, Ying Xu, Donghai Zhao, Lianwen Zheng
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Asherman syndrome (AS) has an adverse effect on reproductive health and fertility by affecting endometrial regeneration. Stem cell-based therapies hold promise for future use in activating non-functional endometrium and reconstructing the endometrium in vivo. It has been postulated that various endometrial stem cells (EnSCs) are responsible for endometrial regeneration. Numerous studies have focused on bone marrow-derived stem cells (BMDSCs), which may provide new ideas for repairing endometrial lesions and reconstructing the endometrium. Other sources of stem cells, such as menstrual blood, umbilical cord, and amniotic membrane, have also attracted much attention as candidates for transplantation in AS. This review discusses the features and specific biomarkers among four types of resident endometrial stem cells, applications of four different sources of exogenous stem cells in AS, and development of stem cell therapy using biomaterials and exosomes.
      Citation: Cell Transplantation
      PubDate: 2021-06-09T09:13:20Z
      DOI: 10.1177/09636897211020734
      Issue No: Vol. 30 (2021)
  • Platelet Mitochondria Transplantation Rescues
           Hypoxia/Reoxygenation-Induced Mitochondrial Dysfunction and Neuronal Cell
           Death Involving the FUNDC2/PIP3/Akt/FOXO3a Axis

    • Authors: Chun Shi, Han Guo, Xintong Liu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Mitochondrial transplantation emerges as a novel therapeutic solution for ischemia/reperfusion injury (IRI) in various tissues. Platelets have recently been used in mitochondrial transplantation as readily-available donors of small-size platelet mitochondria (plt-mito). Interestingly, FUN14 Domain Containing 2 (FUNDC2), a protein highly-expressed in the outer membrane (OMM) of plt-mito, has been identified to maintain platelet survival under hypoxic condition. The current study determined whether and how FUNDC2 contributed to the therapeutic effect of plt-mito transplantation for hypoxia/reoxygenation (HR) injury. The results showed that incorporation of human plt-mito into SH-SY5Y cells rescued HR-induced mitochondrial malfunction and mitochondrial apoptotic pathway. Mechanistically, plt-mito transplantation led to an increased expression of FUNDC2 in the recipient cells. This protein induced mitochondrial translocation of phosphatidylinositol-3,4,5-trisphosphate (PIP3) via its N-term, resulting in the stimulation of the protein kinase B (Akt)/forkhead box O3a (FOXO3a) pathway, which inhibited HR-induced mitochondrial accumulation of a mitochondrial target of FOXO3a, Bim, also known as a pro-apoptotic protein. Therefore, the FUNDC2/PIP3/Akt/FOXO3a axis may facilitate the incorporated plt-mito to restore mitochondrial function and cell viability of the recipient cells, and platelets may serve as readily-available sources of donor mitochondria that afford therapeutic benefits against IRI.
      Citation: Cell Transplantation
      PubDate: 2021-06-09T09:13:19Z
      DOI: 10.1177/09636897211024210
      Issue No: Vol. 30 (2021)
  • Long-Term Outcome of Sciatic Nerve Regeneration Using Bio3D Conduit
           Fabricated from Human Fibroblasts in a Rat Sciatic Nerve Model

    • Authors: Maki Ando, Ryosuke Ikeguchi, Tomoki Aoyama, Mai Tanaka, Takashi Noguchi, Yudai Miyazaki, Shizuka Akieda, Koichi Nakayama, Shuichi Matsuda
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Previously, we developed a Bio3D conduit fabricated from human fibroblasts and reported a significantly better outcome compared with artificial nerve conduit in the treatment of rat sciatic nerve defect. The purpose of this study is to investigate the long-term safety and nerve regeneration of Bio3D conduit compared with treatments using artificial nerve conduit and autologous nerve transplantation.We used 15 immunodeficient rats and randomly divided them into three groups treated with Bio3D (n = 5) conduit, silicon tube (n = 5), and autologous nerve transplantation (n = 5). We developed Bio3D conduits composed of human fibroblasts and bridged the 5 mm nerve gap created in the rat sciatic nerve. The same procedures were performed to bridge the 5 mm gap with a silicon tube. In the autologous nerve group, we removed the 5 mm sciatic nerve segment and transplanted it. We evaluated the nerve regeneration 24 weeks after surgery.Toe dragging was significantly better in the Bio3D group (0.20 ± 0.28) than in the silicon group (0.6 ± 0.24). The wet muscle weight ratios of the tibial anterior muscle of the Bio3D group (79.85% ± 5.47%) and the autologous nerve group (81.74% ± 2.83%) were significantly higher than that of the silicon group (66.99% ± 3.51%). The number of myelinated axons and mean myelinated axon diameter was significantly higher in the Bio3D group (14708 ± 302 and 5.52 ± 0.44 μm) and the autologous nerve group (14927 ± 5089 and 6.04 ± 0.85 μm) than the silicon group (7429 ± 1465 and 4.36 ± 0.21 μm). No tumors were observed in any of the rats in the Bio3D group at 24 weeks after surgery.The Bio3D group showed significantly better nerve regeneration and there was no significant difference between the Bio3D group and the nerve autograft group in all endpoints.
      Citation: Cell Transplantation
      PubDate: 2021-06-09T09:13:17Z
      DOI: 10.1177/09636897211021357
      Issue No: Vol. 30 (2021)
  • Combined Use of Tocilizumab and Mesenchymal Stromal Cells in the Treatment
           of Severe Covid-19: Case Report

    • Authors: Alexandra Cristina Senegaglia, Carmen Lúcia Kuniyoshi Rebelatto, Claudio Luciano Franck, Juliana Souza Lima, Lidiane Maria Boldrini-Leite, Debora Regina Daga, Cleverson Alex Leitão, Patrícia Shigunov, Ana Paula de Azambuja, Elisa Bana, Daniela Boscaro Marsaro, Bruna Schaidt, Andressa Micosky, Valderez Ravaglio Jamur, Yara Schluga, Isadora May Vaz, Lisandro Lima Ribeiro, Alejandro Correa, e Paulo Roberto Slud Brofman
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The coronavirus pandemic is one of the most significant public health events in recent history. Currently, no specific treatment is available. Some drugs and cell-based therapy have been tested as alternatives to decrease the disease’s symptoms, length of hospital stay, and mortality. We reported the case of a patient with a severe manifestation of COVID-19 in critical condition who did not respond to the standard procedures used, including six liters of O2 supplementation under a nasal catheter and treatment with dexamethasone and enoxaparin in prophylactic dose. The patient was treated with tocilizumab and an advanced therapy product based on umbilical cord-derived mesenchymal stromal cells (UC-MSC). The combination of tocilizumab and UC-MSC proved to be safe, with no adverse effects, and the results of this case report prove to be a promising alternative in the treatment of patients with severe acute respiratory syndrome due to SARS-CoV-2.
      Citation: Cell Transplantation
      PubDate: 2021-06-02T06:23:20Z
      DOI: 10.1177/09636897211021008
      Issue No: Vol. 30 (2021)
  • Long-Term Observation and Sequencing Analysis of SKPs-Derived Corneal
           Endothelial Cell-Like Cells for Treating Corneal Endothelial Dysfunction

    • Authors: Lin Shen, Peng Sun, Liqun Du, Jing Zhu, Chengqun Ju, Hui Guo, Xinyi Wu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Corneal endothelial dysfunction is a principal cause of visual deficiency. Corneal transplantation is the most effective treatment for corneal endothelial dysfunction. However, a severe shortage of available donor corneas or human corneal endothelial cells (HCECs) remains a global challenge. Previously, we acquired corneal endothelial cell-like cells (CEC-like cells) derived from human skin-derived precursors (SKPs). CEC-like cells were injected into rabbit and monkey corneal endothelial dysfunction models and exerted excellent therapeutic effect. In this study, we prolonged the clinical observation in the monkey experiment for 2 years. Polymerase chain reaction (PCR) and DNA sequencing were carried out to confirm the existence of CEC-like cells. Histological examinations were carried out to show the corneal morphology. Further transcriptome sequencing was also carried out on HCEC, CEC-like cells before transplantation and after transplantation. We found that the monkeys cornea remained transparent and normal thickness. The total endothelial cell density decreased gradually, but tended to be stable and remained in a normal range during 2-year observation. The CEC-like cells persist during observation and could adapt to the microenvironment after transplantation. The gene expression pattern of CEC-like cells was similar to HCEC and changed slightly after transplantation. In conclusion, this study presented a brand-new insight into CEC-like cells and further provided a promising prospect of cell-based therapy for corneal endothelial dysfunction. The renewable cell source, novel derivation method and simple treatment strategy may be clinically applied in regenerative medicine in the future.
      Citation: Cell Transplantation
      PubDate: 2021-05-31T08:18:01Z
      DOI: 10.1177/09636897211017830
      Issue No: Vol. 30 (2021)
  • The Developmental & Molecular Requirements for Ensuring that Human
           Pluripotent Stem Cell-Derived Hair Follicle Bulge Stem Cells Have Acquired
           Competence for Hair Follicle Generation Following Transplantation

    • Authors: Michel R. Ibrahim, Walid Medhat, Hasan El-Fakahany, Hamza Abdel-Raouf, Evan Y. Snyder
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      When using human induced pluripotent stem cells (hiPSCs) to achieve hair follicle (HF) replacement, we found it best to emulate the earliest fundamental developmental processes of gastrulation, ectodermal lineage commitment, and dermogenesis. Viewing hiPSCs as a model of the epiblast, we exploited insights from mapping the dynamic up- and down-regulation of the developmental molecules that determine HF lineage in order to ascertain the precise differentiation stage and molecular requirements for grafting HF-generating progenitors. To yield an integrin-dependent lineage like the HF in vivo, we show that hiPSC derivatives should co-express, just prior to transplantation, the following combination of markers: integrins α6 and β1 and the glycoprotein CD200 on their surface; and, intracellularly, the epithelial marker keratin 18 and the hair follicle bulge stem cell (HFBSC)-defining molecules transcription factor P63 and the keratins 15 and 19. If the degree of trichogenic responsiveness indicated by the presence of these molecules is not achieved (they peak on Days 11-18 of the protocol), HF generation is not possible. Conversely, if differentiation of the cells is allowed to proceed beyond the transient intermediate progenitor state represented by the HFBSC, and instead cascades to their becoming keratin 14+ keratin 5+ CD200– keratinocytes (Day 25), HF generation is equally impossible. We make the developmental case for transplanting at Day 16-18 of differentiation—the point at which the hiPSCs have lost pluripotency, have attained optimal expression of HFBSC markers, have not yet experienced downregulation of key integrins and surface glycoproteins, have not yet started expressing keratinocyte-associated molecules, and have sufficient proliferative capacity to allow a well-populated graft. This panel of markers may be used for isolating (by cytometry) HF-generating derivatives away from cell types unsuited for this therapy as well as for identifying trichogenic drugs.
      Citation: Cell Transplantation
      PubDate: 2021-05-31T08:18:00Z
      DOI: 10.1177/09636897211014820
      Issue No: Vol. 30 (2021)
  • In Vitro Characterization of Poly(Lactic Acid)/ Poly(Hydroxybutyrate)/
           Thermoplastic Starch Blends for Tissue Engineering Application

    • Authors: Martina Culenova, Ivana Birova, Pavol Alexy, Paulina Galfyova, Andreas Nicodemou, Barbora Moncmanova, Roderik Plavec, Katarina Tomanova, Premysl Mencik, Stanislav Ziaran, Lubos Danisovic
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Complex in vitro characterization of a blended material based on Poly(Lactic Acid), Poly(Hydroxybutyrate), and Thermoplastic Starch (PLA/PHB/TPS) was performed in order to evaluate its potential for application in the field of tissue engineering. We focused on the biological behavior of the material as well as its mechanical and morphological properties. We also focused on the potential of the blend to be processed by the 3D printer which would allow the fabrication of the custom-made scaffold. Several blends recipes were prepared and characterized. This material was then studied in the context of scaffold fabrication. Scaffold porosity, wettability, and cell-scaffold interaction were evaluated as well. MTT test and the direct contact cytotoxicity test were applied in order to evaluate the toxic potential of the blended material. Biocompatibility studies were performed on the human chondrocytes. According to our results, we assume that material had no toxic effect on the cell culture and therefore could be considered as biocompatible. Moreover, PLA/PHB/TPS blend is applicable for 3D printing. Printed scaffolds had highly porous morphology and were able to absorb water as well. In addition, cells could adhere and proliferate on the scaffold surface. We conclude that this blend has potential for scaffold engineering.
      Citation: Cell Transplantation
      PubDate: 2021-05-31T07:22:13Z
      DOI: 10.1177/09636897211021003
      Issue No: Vol. 30 (2021)
  • Immunosuppressant Drugs Mitigate Immune Responses Generated by Human
           Mesenchymal Stem Cells Transplanted into the Mouse Parenchyma

    • Authors: Jung Won Hwang, Su Hyeon Myeong, Na-Hee Lee, Hyeongseop Kim, Hyo Jin Son, Jong Wook Chang, Na Kyung Lee, Duk L. Na
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      It has been widely accepted that mesenchymal stem cells (MSCs) can evade the immune surveillance of the recipient. However, emerging research cast doubt on whether MSCs are intrinsically immune-privileged. Previously, we observed that the transplantation of human MSCs (hMSCs) into the mouse parenchyma attracted a high infiltration of leukocytes into the injection tract. Thus, in order to reduce the immune responses generated by hMSCs, the aim of this study was to assess which immunosuppressant condition (dexamethasone only, tacrolimus only, or dexamethasone and tacrolimus together) would not only reduce the overall immune response but also enhance the persistence of MSCs engrafted into the caudate putamen of wild-type C57BL/6 mice. According to immunohistochemical analysis, compared to the hMSC only group, the administration of immunosuppressants (for all three conditions) reduced the infiltration of CD45-positive leukocytes and neutrophils at the site of injection. The highest hMSC persistence was detected from the group that received combinatorial administrations of dexamethasone and tacrolimus. Moreover, compared to the immunocompetent WT mouse, higher MSC engraftment was observed from the immunodeficient BALB/c mice. The results of this study support the use of immunosuppressants to tackle MSC-mediated immune responses and to possibly prolong the engraftment of transplanted MSCs.
      Citation: Cell Transplantation
      PubDate: 2021-05-28T08:56:42Z
      DOI: 10.1177/09636897211019025
      Issue No: Vol. 30 (2021)
  • Selecting a Cell Engineering Methodology During Cell Therapy Product

    • Authors: Lauren M. Timmins, Alexandra M. Burr, Kristina Carroll, Robert Keefe, Matthew Teryek, Louis J. Cantolupo, Johannes C. M. van der Loo, Thomas R.J. Heathman, Adam Gormley, David Smith, Biju Parekkadan
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      When considering the development pathway for a genetically modified cell therapy product, it is critically important that the product is engineered consistent with its intended human use. For scientists looking to develop and commercialize a new technology, the decision to select a genetic modification method depends on several practical considerations. Whichever path is chosen, the developer must understand the key risks and potential mitigations of the cell engineering approach. The developer should also understand the clinical implications: permanent/memory establishment versus transient expression, and clinical manufacturing considerations when dealing with transplantation of genetically engineered cells. This review covers important topics for mapping out a strategy for developers of new cell-based therapeutics. Biological, technological, manufacturing, and clinical considerations are all presented to map out development lanes for the initiation and risk management of new gene-based cell therapeutic products for human use.
      Citation: Cell Transplantation
      PubDate: 2021-05-20T11:15:56Z
      DOI: 10.1177/09636897211003022
      Issue No: Vol. 30 (2021)
  • Comparison and Investigation of Exosomes Derived from Platelet-Rich Plasma
           Activated by Different Agonists

    • Authors: Shunli Rui, Yi Yuan, Chenzhen Du, Peiyang Song, Yan Chen, Hongyan Wang, Yahan Fan, David G. Armstrong, Wuquan Deng, Ling Li
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      PRP-Exos are nanoscale cup-shaped vesicles that carry a variety of proteins, mRNAs, microRNAs, and other bioactive substances. PRP-Exos can be formed through several induction pathways, which determine their molecular profiles and facilitate their tailormade participation in intercellular communication. Currently, little is known on how the PRP-Exos activation method influences the quality and quantity of PRP-Exos. The present study aims to observe and analyze the number, profile, and growth factors of PRP-Exos through TEM, Nanoflow, and WB after PRP activation and compare the difference in function of PRP-Exos on HUVECs, with different stimuli (calcium gluconate, thrombin, or both). We found that PRP activated with both thrombin and calcium gluconate harvested the highest concentration of exosomes [(7.16 ± 0.46) × 1010 particles/ml], compared to thrombin group [(4.87 ± 0.15) × 1010 particles/ml], calcium gluconate group [(5.85 ± 0.43) × 1010 particles/ml], or saline group [(7.52 ± 0.19) × 109 particles/ml], respectively (P < 0.05) via Nanoflow analysis. The WB analysis showed that cytokines (VEGF, PDGFBB, bFGF, TGF-β) are differentially encapsulated in PRP-Exos, depending on the PRP stimulus, in which the mixture-PRP-Exos yielded the highest concentration of cytokines. In the function assay of PRP-Exos on HUVECs, the mixture-PRP-Exos promoted HUVECs proliferation, increased HUVECs migration, promoted the formation of vessel-like by HUVECs via the AKT ERK signal pathway more dramatically, compared with other groups. In summary, our studies showed that PRP activated by the mixture of calcium gluconate and thrombin harvested the best quality of exosomes which had the top biological functions. This study provides a protocol for selecting appropriate PRP activators to obtain high-quality exosomes for future applications.
      Citation: Cell Transplantation
      PubDate: 2021-05-19T07:00:47Z
      DOI: 10.1177/09636897211017833
      Issue No: Vol. 30 (2021)
  • To Research the Effects of Storage Time on Autotransfusion based on

    • Authors: Zhen-Zhou Li, Dong-Lin Jia, Huan Wang, Xiao-Fang Zhou, Yong Cheng, Li-Shuang Duan, Lei Yin, Han-Wei Wei, Wei Guo, Jian-Rong Guo
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Autotransfusion refers to a blood transfusion method in which the blood or blood components of the patient are collected under certain conditions, returned to himself when the patient needs surgery or emergency after a series of storing and processing. Although autotransfusion can avoid blood-borne diseases and adverse reactions related to allogeneic blood transfusion, a series of structural and functional changes of erythrocytes will occur during extension of storage time, thus affecting the efficacy of clinical blood transfusion. Our research was aimed to explore the change of erythrocyte oxygen-carrying capacity in different storage time, such as effective oxygen uptake (Q), P50, 2,3-DPG, Na+-K+-ATPase, to detect membrane potential, the change of Ca2+, and reactive oxygen species (ROS) change of erythrocytes. At the same time, Western blot was used to detect the expression of Mitofusin 1 (Mfn1) and Mitofusin 2 (Mfn2) proteins on the cytomembrane, from the perspective of oxidative stress to explore the function change of erythrocytes after different storage time. This study is expected to provide experimental data for further clarifying the functional status of erythrocytes with different preservation time in patients with autotransfusion, achieving accurate infusion of erythrocytes and improving the therapeutic effect of autologous blood transfusion, which has important clinical application value.
      Citation: Cell Transplantation
      PubDate: 2021-05-18T06:44:25Z
      DOI: 10.1177/09636897211005683
      Issue No: Vol. 30 (2021)
  • Utilizing Xenogeneic Cells As a Therapeutic Agent for Treating Diseases

    • Authors: Chi-Ping Huang, Chi-Yu Yang, Chih-Rong Shyr
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The utilization of biologically produced cells to treat diseases is a revolutionary invention in modern medicine after chemically synthesized small molecule drugs and biochemically made protein drugs. Cells are basic units of life with diverse functions in mature and developing organs, which biological properties could be utilized as a promising therapeutic approach for currently intractable and incurable diseases. Xenogeneic cell therapy utilizing animal cells other than human for medicinal purpose has been studied as a new way of treating diseases. Xenogeneic cell therapy is considered as a potential regenerative approach to fulfill current unmet medical needs because xenogeneic cells could be isolated from different animal organs and expanded ex vivo as well as maintain the characteristics of original organs, providing a versatile and plenty cell source for cell-based therapeutics beside autologous and allogeneic sources. The swine species is considered the most suitable source because of the similarity with humans in size and physiology of many organs in addition to the economic and ethical reasons plus the possibility of genetic modification. This review discusses the old proposed uses of xenogeneic cells such as xenogeneic pancreatic islet cells, hepatocytes and neuronal cells as a living drug for the treatment of degenerative and organ failure diseases. Novel applications of xenogeneic mesenchymal stroma cells and urothelial cells are also discussed. There are formidable immunological barriers toward successful cellular xenotransplantation in clinic despite major progress in the development of novel immunosuppression regimens and genetically multimodified donor pigs. However, immunological barriers could be turn into immune boosters by using xenogeneic cells of specific tissue types as a novel immunotherapeutic agent to elicit bystander antitumor immunity due to rejection immune responses. Xenogeneic cells have the potential to become a safe and efficacious option for intractable diseases and hard-to-treat cancers, adding a new class of cellular medicine in our drug armamentarium.
      Citation: Cell Transplantation
      PubDate: 2021-05-12T08:50:32Z
      DOI: 10.1177/09636897211011995
      Issue No: Vol. 30 (2021)
  • Targeting Matrix Metalloproteinases: A Potential Strategy for Improving
           Cell Transplantation for Nervous System Repair

    • Authors: Yu-Ting Tseng, Mo Chen, James St John, Jenny Ekberg
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Cell transplantation shows promise for repair of the injured nervous system, including spinal cord injury (SCI) and peripheral nerve injury (PNI). There are, however, still problems hampering these therapies moving from bench to bedside, and the methods need optimization. Three-dimensional (3D) cell culture systems are suggested to improve outcomes, bridging the gap between the in vitro and in vivo environments. In such constructs, cells are allowed to interact with each other and with the extracellular matrix (ECM) in 3D as they do in vivo. Transplanting cells in 3D constructs, rather than in suspension, is thought to promote cell survival and maintain important cellular behaviors. One such critical behavior is cell migration into and within the injury site. Understanding and controlling the migratory capability of 3D-cultured cells is therefore pivotal for developing better transplantation techniques. ECM remodelling can influence numerous cellular functions, including cell migration and matrix metalloproteinases (MMPs) are important enzymes for ECM modulation. Here, we discuss the idea of modulating MMPs to control cell migration in 3D culture systems, which can improve the therapeutic potential of cells transplanted in 3D.
      Citation: Cell Transplantation
      PubDate: 2021-05-12T05:28:59Z
      DOI: 10.1177/09636897211012909
      Issue No: Vol. 30 (2021)
  • Wound Healing by Allogeneic Transplantation of Specific Subpopulation From
           Human Umbilical Cord Mesenchymal Stem Cells

    • Authors: María Belén Palma, Carlos Luzzani, Laura B. Andrini, Fernando Riccillo, Guillermo Buero, Pablo Pelinski, Ana M Inda, Ana Lía Errecalde, Santiago Miriuka, Edgardo D. Carosella, Marcela N. Garcia
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      In normal physiological conditions, restoration of a functional epidermal barrier is highly efficient; nevertheless, when it fails, one of the main consequences is a chronic ulcerative skin defect, one of the most frequently recognized complications of diabetes. Most of these chronic venous ulcers do not heal with conventional treatment, leading to the appearance of infections and complications in the patient. Treatments based on the use of autologous mesenchymal stem cells (MSC) have been successful; however, its implementation entails complications. The umbilical cord offers an unlimited source of adult MSC (ucMSC) from the Wharton’s jelly tissue with the same relevant features for clinical applicability and avoiding difficulties. It has recently been characterized by one specific subpopulation derived from ucMSC, the differentiated mesenchymal cells (DMCs). This subpopulation expresses the human leukocyte antigen-G (HLA-G) molecule, a strong immunosuppressive checkpoint, and vascular endothelial growth factor (VEGF), the most potent angiogenic factor. Considering the importance of developing a more effective therapy for wound treatment, especially ulcerative skin lesions, we analyzed DMC safety, efficacy, and therapeutic potential. By immunohistochemistry, umbilical cords HLA-G and VEGF positive were selected. Flow cytometry revealed that 90% of the DMC subpopulation are HLA-G+, CD44+, CD73+, CD29+, CD105+, CD90+, and HLA-DR−. Reverse transcription-polymerase chain reaction revealed the expression of HLA-G in all of DMC subpopulations. Upon co-culture with the DMC, peripheral blood mononuclear cell proliferation was inhibited by 50%. In a xenograft transplantation assay, DMC improved wound healing with no signs of rejection of the transplanted cells in immunocompetent mice. This study confirms that HLA-G allows allogeneic cell transplantation, and VEGF is fundamental for the restoration of the failure in blood supply. DMC population has positive effects on wound healing by promoting local angiogenesis in skin lesions. DMC could play a very important role in regenerative medicine and could be a novel allogeneic cell-therapeutic tool for wound healing.
      Citation: Cell Transplantation
      PubDate: 2021-05-12T05:28:59Z
      DOI: 10.1177/0963689721993774
      Issue No: Vol. 30 (2021)
  • Impact of One Versus Two Consecutive Doses of Endothelial Cells (EPCs) and
           EPCs-Derived Condition Medium on Protecting Myocardium from Acute
           Ischemia-Reperfusion Injury in Rat

    • Authors: Jui-Ning Yeh, Ruan-Ruan Yang, Christopher Glenn Wallace, Chi-Ruei Huang, Yi-Ching Chu, Hon-Kan Yip, Jun Guo
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      This study tested the impact of single dose and two doses of endothelial progenitor cells (EPCs) and EPCs-derived condition medium (CM) on protecting the left-ventricular myocardium (LVM) from acute ischemia-reperfusion (IR) injury. In vitro study showed EPCs and CM had comparably higher capacity for enhancement of angiogenesis as compared with the controls (all P < .001). Adult-male SD rats (n = 36) were equally categorized into groups 1 (sham-operated control), 2 (IR+vehicle), 3 [IR+EPCs/1.2 × 106/intravenous administration at 3 h after IR procedure), 4 (IR+EPCs/1.2 × 106/at 3 h/24 h after IR), 5 (IR+CM/3.0cc/intravenous administration at 3 h after IR), 6 (IR+EPCs/3.0cc/at 3h/24 h after IR), and euthanized by day 3 after IR. The left-ventricular-ejection-fraction, protein and cellular expressions of endothelial-cell markers (CD31/vWF), small vessel number and protein expression of mitochondrial (mitochondrial-cytochrome-C) integrity were highest in group 1, lowest in group 2, significantly higher in group 4 than in groups 3/5/6 and significantly higher in groups 3/6 than in group 5 but they showed no differences in groups3/6, whereas the protein expressions of apoptotic (cleaved-caspase 3/cleaved-PARP), fibrotic (Smad3/TGF-ß), mitochondrial-damaged (cytosolic-cytochrome-C), heart-failed/pressure-overload (BNP), oxidative-stress (p47phox/NOX-1/NOX-2/oxidized protein), and autophagic (LCB3-II/LCB3-I) biomarkers and fibrotic/collagen-deposition areas exhibited an opposite pattern to endothelial-cell markers (all P < .0001). The protein expressions of angiogenesis (VEGF/SDF-1α/CXCR4/HIF-1α) were lowest in group 1, highest in group 4, significantly higher in groups 3/6 than in groups 2/5, significantly higher in group 5 than in group 2, but they showed no difference between groups 3/6 (all P < .0001). These results demonstrate that two consecutive doses of EPC/CM were superior to just one at protecting LVM against IR injury.
      Citation: Cell Transplantation
      PubDate: 2021-05-12T05:28:58Z
      DOI: 10.1177/09636897211007049
      Issue No: Vol. 30 (2021)
  • Role of the Immune Microenvironment in SARS-CoV-2 Infection

    • Authors: Chih-Hung Ye, Wen-Lin Hsu, Guan-Ru Peng, Wei-Chieh Yu, Wei-Chen Lin, SuiYun Hu, Shu-Han Yu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Severe acute respiratory syndrome coronavirus (SARS-CoV-2) first emerged in December 2019 in Wuhan, China, and has since spread rapidly worldwide. As researchers seek to learn more about COVID-19, the disease it causes, this novel virus continues to infect and kill. Despite the socioeconomic impacts of SARS-CoV-2 infections and likelihood of future outbreaks of other pathogenic coronaviruses, options to prevent or treat coronavirus infections remain limited. In current clinical trials, potential coronavirus treatments focusing on killing the virus or on preventing infection using vaccines largely ignore the host immune response. The relatively small body of current research on the virus indicates pathological responses by the immune system as the leading cause for much of the morbidity and mortality caused by COVID-19. In this review, we investigated the host innate and adaptive immune responses against COVID-19, collated information on recent COVID-19 experimental data, and summarized the systemic immune responses to and histopathology of SARS-CoV-2 infection. Finally, we summarized the immune-related biomarkers to define patients with high-risk and worst-case outcomes, and identified the possible usefulness of inflammatory markers as potential immunotherapeutic targets. This review provides an overview of current knowledge on COVID-19 and the symptomatological differences between healthy, convalescent, and severe cohorts, while offering research directions for alternative immunoregulation therapeutic targets.
      Citation: Cell Transplantation
      PubDate: 2021-05-05T09:47:23Z
      DOI: 10.1177/09636897211010632
      Issue No: Vol. 30 (2021)
  • Pilot Study of Endovascular Delivery of Mesenchymal Stromal Cells in the
           Aortic Wall in a Pig Model

    • Authors: Ke Li, Deborah Vela, Elton Migliati, Maria da Graca Cabreira, Xiaohong Wang, L Maximilian Buja, Emerson C. Perin
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Abdominal aortic aneurysms (AAAs) have a high mortality. In small-animal models, multipotent mesenchymal stromal cells (MSCs) have shown benefits in attenuating aneurysm formation. However, an optimal cell delivery strategy is lacking. The NOGA system, which targets cell injections in a less-invasive way, has been used for myocardial cell delivery. Here, we assessed the safety and feasibility of the NOGA system for endovascular delivery of MSCs to the aortic wall in an AAA pig model. We induced AAA in 9 pigs by surgery or catheter induction. MSCs were delivered using the NOGA system 6 or 8 weeks after aneurysm induction. We euthanized the pigs and harvested the aorta for histologic analysis 1, 3, and 7 days after cell delivery. During AAA creation, 1 pig died; 8 pigs completed the study without acute adverse events or complications. The cell delivery procedure was safe and feasible. We successfully injected MSCs directly into the aortic wall in a targeted manner. Histologic and immunohistochemical analyses confirmed transmural injections in the aortic wall area of interest and the presence of MSCs. Our study showed the safety and feasibility of endovascular cell delivery to the aortic wall in a pig model.
      Citation: Cell Transplantation
      PubDate: 2021-05-03T01:38:33Z
      DOI: 10.1177/09636897211010652
      Issue No: Vol. 30 (2021)
  • Sexual Dimorphism in Hepatocyte Xenograft Models

    • Authors: Gulce Sari, Gertine W. van Oord, Martijn D.B. van de Garde, Jolanda J.C. Voermans, Andre Boonstra, Thomas Vanwolleghem
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Humanized liver mouse models are crucial tools in liver research, specifically in the fields of liver cell biology, viral hepatitis and drug metabolism. The livers of these humanized mouse models are repopulated by 3-dimensional islands of fully functional primary human hepatocytes (PHH), which are notoriously difficult to maintain in vitro. As low efficiency and high cost hamper widespread use, optimization is of great importance. In the present study, we analyzed experimental factors associated with Hepatitis E virus (HEV) infection and PHH engraftment in 2 xenograft systems on a Nod-SCID-IL2Ry-/- background: the alb-urokinase plasminogen activator mouse model (uPA-NOG, n=399); and the alb-HSV thymidine kinase model (TK-NOG, n = 198). In a first analysis, HEV fecal shedding in liver humanized uPA-NOG and TK-NOG mice with comparable human albumin levels was found to be similar irrespective of the mouse genetic background. In a second analysis, sex, mouse age at transplantation and hepatocyte donor were the most determinant factors for xenograft success in both models. The sexual imbalance for xenograft success was related to higher baseline ALT levels and lower thresholds for ganciclovir induced liver morbidity and mortality in males. These data call for sexual standardization of human hepatocyte xenograft models, but also provide a platform for further studies on mechanisms behind sexual dimorphism in liver diseases.
      Citation: Cell Transplantation
      PubDate: 2021-05-02T10:11:57Z
      DOI: 10.1177/09636897211006132
      Issue No: Vol. 30 (2021)
  • Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the
           University of Chicago: Additional Standardizations of Trial Protocol are
           Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet

    • Authors: Piotr J. Bachul, Karolina Golab, Lindsay Basto, Steven Zangan, Jordan S. Pyda, Angelica Perez-Gutierrez, Peter Borek, Ling-Jia Wang, Martin Tibudan, Dong-Kha Tran, Roi Anteby, Gabriela S. Generette, Jędrzej Chrzanowski, Wojciech Fendler, Laurencia Perea, Kumar Jayant, Aaron Lucander, Celeste Thomas, Louis Philipson, J. Michael Millis, John Fung, Piotr Witkowski
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin (N = 8) or placebo (N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years (P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group (n = 7) than in the placebo (n = 3) group (P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT (P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959,
      Citation: Cell Transplantation
      PubDate: 2021-04-28T09:30:55Z
      DOI: 10.1177/09636897211001774
      Issue No: Vol. 30 (2021)
  • Circulating miRNA in Patients Undergoing Total Pancreatectomy and Islet

    • Authors: Srividya Vasu, Jiemin M. Yang, James Hodges, Maisam A. Abu-El-Haija, David B. Adams, Appakalai N. Balamurugan, Greg J. Beilman, Srinath Chinnakotla, Darwin L. Conwell, Martin L. Freeman, Timothy B. Gardner, Betul Hatipoglu, Varvara Kirchner, Luis F. Lara, Katherine A. Morgan, Jaimie D. Nathan, Andrew Posselt, Timothy L. Pruett, Sarah J. Schwarzenberg, Vikesh K. Singh, Martin Wijkstrom, Piotr Witkowski, Bashoo Naziruddin, Melena D. Bellin
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples (n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p (P = 0.03), hsa-miR-148a-3p (P = 0.04) and hsa-miR-221-3p (P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p (P = 0.04) and hsa-miR-7-5p (P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p (P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p (P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg (r = −0.20, P = 0.02). Also, hsa-miR-200c (r = 0.18, P = 0.03) and hsa-miR-221-3p (r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.
      Citation: Cell Transplantation
      PubDate: 2021-04-27T08:11:04Z
      DOI: 10.1177/0963689721999330
      Issue No: Vol. 30 (2021)
  • Ginsenoside Rb1 Alleviates Lipopolysaccharide-Induced Inflammatory Injury
           by Downregulating miR-222 in WI-38 Cells

    • Authors: Erhu Wei, Xiao Fang, Peisheng Jia, Mingxia Li, Peina Jin, Fengyan Li, Huaili Wang, Dan Gao
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Pneumonia is a serious respiratory tract infection disease in children, which threatens to the health or life of children patients. Ginsenoside Rb1 (Rb1) is a principle active ingredient extracted from the root of Panax notoginseng (Burk.) F.H. Chen with anti-inflammatory effect. Our study aimed to determine the effects and molecular mechanisms of Rb1 on lipopolysaccharide (LPS)-induced inflammatory injury of lung fibroblasts WI-38 cells. Cell viability and apoptosis were evaluated by CCK-8 and flow cytometry, respectively. The production of inflammatory cytokines were measured by ELISA and RT-qPCR. miR-222 expression was examined by RT-qPCR. The expression levels of the nuclear factor-kappa B (NF-κB) p65 and phosphorylated p65 were detected by western blot. We found that LPS stimulation induced WI-38 cell inflammatory injury by inhibiting cell viability, and inducing apoptosis and inflammatory cytokine production, while treatment with Rb1 significantly attenuated LPS-induced inflammatory injury in WI-38 cells. Additionally, Rb1 decreased LPS-induced upregulation of miR-222 and activation of the NF-κB pathway in WI-38 cells. Overexpression of miR-222 abolished the inhibitory effects of Rb1 on LPS-induced viability reduction, apoptosis, inflammatory cytokine production and activation of the NF-κB pathway. In conclusion, Rb1 alleviated LPS-induced inflammatory injury in WI-38 cells via downregulating miR-222 and inactivation of the NF-kB pathway.
      Citation: Cell Transplantation
      PubDate: 2021-04-26T03:22:46Z
      DOI: 10.1177/09636897211002787
      Issue No: Vol. 30 (2021)
  • Clonal Architectures Predict Clinical Outcome in Gastric Adenocarcinoma
           Based on Genomic Variation, Tumor Evolution, and Heterogeneity

    • Authors: Chenxia Ren, Cuiling Wu, Niuniu Wang, Changhong Lian, Changqing Yang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Stomach adenocarcinoma (STAD) is a highly heterogeneous disease. Due to the lack of effective molecular markers and personalized treatment, the prognosis of gastric cancer patients is still very poor. The ABSOLUTE algorithm and cancer cell fraction were used to evaluate the clonal and subclonal status of 349 TCGA (The Cancer Genome Cancer Atlas)-STAD patients. Non-negative matrix factorization was used to identify the mutation characteristics of the samples. Univariate Cox regression analysis was used to determine the relationship between clonal/subclonal events and prognosis, and the Spearman correlation was used to evaluate the relationship of clonal/subclonal events to tumor mutation burden (TMB) and neoantigens. The evolution pattern of STAD demonstrated great tumor heterogeneity. TP53, USH2A, and GLI3 appeared earliest in STAD and may drive STAD. CTNNB1, LRP1B, and ERBB4 appeared the latest in STAD, and may be related to STAD’s progress. Univariate Cox regression analysis identified four early genes, eight intermediate genes, and seven late genes significantly associated with overall survival. The number of subclonal events in the T stage was significantly different. The N stage, gender, and histological type were significantly different for clonal events, and there was a significant correlation between clonal/subclonal events and TMB/neoantigens. Our results highlight the importance of systematic evaluation of evolutionary models in the clinical management of STAD and personalized gastric cancer treatment.
      Citation: Cell Transplantation
      PubDate: 2021-04-26T03:22:10Z
      DOI: 10.1177/0963689721989606
      Issue No: Vol. 30 (2021)
  • The Efficacy of the Hepatocyte Spheroids for Hepatocyte Transplantation

    • Authors: Kazuaki Shibuya, Masaaki Watanabe, Ryoichi Goto, Masaaki Zaitsu, Yoshikazu Ganchiku, Akinobu Taketomi
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The safety and short-term efficacy of hepatocyte transplantation (HCTx) have been widely proven. However, issues such as reduced viability and/or function of hepatocytes, insufficient engraftment, and lack of a long-term effect have to be overcome for widespread application of HCTx. In this study, we evaluated hepatocyte spheroids (HSs), formed by self-aggregation of hepatocytes, as an alternative to hepatocytes in single-cell suspension. Hepatocytes were isolated from C57BL/6 J mice liver using a three-step collagenase perfusion technique and HSs were formed by the hanging drop method. After the spheroids formation, the HSs showed significantly higher mRNA expression of albumin, ornithine transcarbamylase, glucose-6-phosphate, alpha-1-antitrypsin, low density lipoprotein receptor, coagulation factors, and apolipoprotein E (ApoE) than 2 dimensional (2D)-cultured hepatocytes (p < 0.05). Albumin production by HSs was significantly higher than that by 2D-cultured hepatocytes (9.5 ± 2.5 vs 3.5 ± 1.8 μg/dL, p < 0.05). The HSs, but not single hepatocytes, maintained viability and albumin mRNA expression in suspension (92.0 ± 2.8% and 1.03 ± 0.09 at 6 h). HSs (3.6 × 106 cells) or isolated hepatocytes (fSH, 3.6 × 106 cells) were transplanted into the liver of ApoE knockout (KO-/-) mice via the portal vein. Following transplantation, serum ApoE concentration (ng/mL) of HS-transplanted mice (1w: 63.1 ± 56.7, 4w: 17.0 ± 10.9) was higher than that of fSH-transplanted mice (1 w: 33.4 ± 13.0, 4w: 13.7 ± 9.6). In both groups, the mRNA levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, MCP-1, and MIP-1β) were upregulated in the liver following transplantation; however, no significant differences were observed. Pathologically, transplanted HSs were observed as flat cell clusters in contact with the portal vein wall on day 7. Additionally, ApoE positive cells were observed in the liver parenchyma distant from the portal vein on day 28. Our results indicate that HS is a promising alternative to single hepatocytes and can be applied for HCTx.
      Citation: Cell Transplantation
      PubDate: 2021-04-26T03:22:09Z
      DOI: 10.1177/09636897211000014
      Issue No: Vol. 30 (2021)
  • Multilayered Human Skeletal Muscle Myoblast Sheets Promote the Healing
           Process After Colonic Anastomosis in Rats

    • Authors: Takashi Nakamura, Utako Yokoyama, Tomomitsu Kanaya, Takayoshi Ueno, Takanori Yoda, Atsushi Ishibe, Yuko Hidaka, Masanari Umemura, Toshio Takayama, Makoto Kaneko, Shigeru Miyagawa, Yoshiki Sawa, Itaru Endo, Yoshihiro Ishikawa
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Colorectal anastomotic leakage is one of the most feared and fatal complications of colorectal surgery. To date, no external coating material that can prevent anastomotic leakage has been developed. As myoblasts possess anti-inflammatory capacity and improve wound healing, we developed a multilayered human skeletal muscle myoblast (HSMM) sheet by periodic exposure to supraphysiological hydrostatic pressure during repeated cell seeding. We assessed whether the application of an HSMM sheet can promote the healing process after colonic anastomosis. Partial colectomy and insufficient suturing were employed to create a high-risk colo-colonic anastomosis model in 60 nude rats. Rats were divided into a control group (n = 30) and an HSMM sheet group (n = 30). Macroscopic findings, anastomotic bursting pressure, and histology at the colonic anastomotic site were evaluated on postoperative day (POD) 3, 5, 7, 14, and 28. The application of an HSMM sheet significantly suppressed abscess formation at the anastomotic site compared to the control group on POD3 and 5. The anastomotic bursting pressure in the HSMM sheet group was higher than that in the control group on POD3 and 5. Inflammatory cell infiltration in the HSMM sheet group was significantly suppressed compared to that in the control group throughout the time course. Collagen deposition in the HSMM sheet group on POD3 was significantly abundant compared to that in the control group. Regeneration of the mucosa at the colonic anastomotic site was promoted in the HSMM sheet group compared to that in the control group on POD14 and 28. Immunohistochemical analysis demonstrated that surviving cells in the HSMM sheet gradually decreased with postoperative time and none were detected on POD14. These results suggest that the application of a multilayered HSMM sheet may prevent postoperative colonic anastomotic leakage.
      Citation: Cell Transplantation
      PubDate: 2021-04-21T11:37:15Z
      DOI: 10.1177/09636897211009559
      Issue No: Vol. 30 (2021)
  • Transdermal Delivery of Adipocyte Phospholipase A2 siRNA using

    • Authors: Guiqin Liu, Yan Deng, Yi Song, Yi Sui, Juan Cen, Ziyu Shao, Hu Li, Tao Tang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Thyroid associated ophthalmopathy (TAO) is an organ-specific autoimmune disease occurring in patients with thyroid disease. Patients with TAO-related proptosis is largely due to excessive orbital adipose tissue Adipocyte phospholipase A2 (AdPLA) is one of the most important regulatory factors in adipocyte lipolysis, which may be associated with TAO-related proptosis. Thus, silencing AdPLA by RNA interference may be beneficial for the treatment of TAO. In this study, we sought to evaluate the efficiency of two types of microneedles to deliver siRNAs for silencing AdPLA. Our results showed that AdPLA mRNA was up-regulated in the orbit adipose tissues from TAO patients. Silence of AdPLA by siRNA can reduce lipid accumulation in both human and mouse adipocyte cell lines. Moreover, silence effects of silicon microneedle array patch-based and injectable microneedle device-based siRNA administration were examined at the belly site of the mice, and injectable microneedle device showed higher knockdown efficiency than silicon microneedle array patch. This study sets the stage not only for future treatment of TAO-related proptosis using AdPLA siRNA, but also provides the foundation for targeted siRNA delivery by using microneedles.
      Citation: Cell Transplantation
      PubDate: 2021-04-21T11:37:14Z
      DOI: 10.1177/09636897211010633
      Issue No: Vol. 30 (2021)
  • Overexpression of FBXO17 Promotes the Proliferation, Migration and
           Invasion of Glioma Cells Through the Akt/GSK-3β/Snail Pathway

    • Authors: Ning Wang, Qian Song, Hai Yu, Gang Bao
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      FBXO17 is a newly studied F-box protein associated with high-grade glioma. However, its exact role in glioma remains unclear. In the present study, we aimed to investigate the role of FBXO17 in glioma both in vitro and in vivo and explore the underlying mechanism. Our results showed that FBXO17 mRNA and protein levels were upregulated in glioma cells including U87, U251, SHG44, and U-118-MG cells as compared to the HA1800 cells. Downregulation of FBXO17 significantly suppressed the cellular behaviors of glioma cells including cell proliferation, migration, and invasion. In addition, FBXO17 knockdown induced E-cadherin expression and inhibited N-cadherin and vimentin expression at mRNA and protein levels in glioma cells. In contrast, overexpression of FBXO17 promoted cell proliferation, migration, invasion and EMT process. Furthermore, FBXO17 regulated the Akt/GSK-3β/snail signaling pathway in glioma cells with significant changes in the expression levels of p-Akt, p-GSK-3β and snail. Additionally, inhibition of Akt by LY294002 reversed the effects of FBXO17 overexpression on cellular behaviors of glioma cells. Finally, in vivo mouse xenograft assay proved that downregulation of FBXO17 suppresses the tumorigenesis of glioma. In conclusion, these findings demonstrated that FBXO17 acted as a promotor of glioma development via modulating Akt/GSK-3β/snail signaling pathway.
      Citation: Cell Transplantation
      PubDate: 2021-04-15T06:14:49Z
      DOI: 10.1177/09636897211007395
      Issue No: Vol. 30 (2021)
  • Recent Findings on Cell-Based Therapies for COVID19-Related Pulmonary

    • Authors: Hong-Meng Chuang, Li-Ing Ho, Horng-Jyh Harn, Ching-Ann Liu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      COVID-19 has spread worldwide, including the United States, United Kingdom, and Italy, along with its site of origin in China, since 2020. The virus was first found in the Wuhan seafood market at the end of 2019, with a controversial source. The clinical symptoms of COVID-19 include fever, cough, and respiratory tract inflammation, with some severe patients developing an acute and chronic lung injury, such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). It has already claimed approximately 300 thousand human lives and the number is still on the rise; the only way to prevent the infection is to be safe till vaccines and reliable treatments develop. In previous studies, the use of mesenchymal stem cells (MSCs) in clinical trials had been proven to be effective in immune modulation and tissue repair promotion; however, their efficacy in treating COVID-19 remains underestimated. Here, we report the findings from past experiences of SARS and MSCs, and how SARS could also induce PF. Such studies may help to understand the rationale for the recent cell-based therapies for COVID-19.
      Citation: Cell Transplantation
      PubDate: 2021-04-13T06:27:06Z
      DOI: 10.1177/0963689721996217
      Issue No: Vol. 30 (2021)
  • Comparison of the Efficacy and Safety of Cell-Assisted Lipotransfer and
           Platelet-Rich Plasma Assisted Lipotransfer: What Should We Expect from a
           Systematic Review with Meta-Analysis'

    • Authors: Aizhen Chen, Li Zhang, Penghong Chen, Chaoyu Zhang, Shijie Tang, Xiaosong Chen
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Due to the high absorption rate of traditional autologous fat grafting, cell-assisted lipotransfer (CAL) and platelet-rich plasma (PRP)-assisted lipotransfer were developed. The purpose of this article was to evaluate the efficacy and safety of CAL and PRP in promoting the survival of autologous fat grafting through systematic review and meta-analysis. We searched Pubmed, Cochrane Library, Web of Science, and EMBASE for clinical studies on CAL and PRP-assisted lipotransfer published from January 2010 to January 2020. Then a meta-analysis was performed to assess the efficacy of CAL and PRP-assisted lipotransfer through data analysis of fat survival rate. We also assessed the incidence of complications and multiple operations to analyze their safety. A total of 36 studies (1697 patients) were included in this review. Regardless of the recipient area, CAL and PRP-assisted lipotransfer significantly improved the fat survival rate (CAL vs non-CAL: 71% vs 48%, P < 0.0001; PRP vs non-PRP: 70% vs 40%, P < 0.0001; CAL vs PRP: 71% vs 70%, P = 0.7175). However, in large-volume fat grafting, such as breast reconstruction, both increased the incidence of complications and did not decrease the frequency of multiple operations after lipotransfer. Further prospective studies are needed to evaluate the clinical benefits of CAL and PRP-assisted lipotransfer.
      Citation: Cell Transplantation
      PubDate: 2021-04-13T06:27:05Z
      DOI: 10.1177/0963689721989607
      Issue No: Vol. 30 (2021)
  • CircANKRD52 Promotes the Tumorigenesis of Hepatocellular Carcinoma by
           Sponging miR-497-5p and Upregulating BIRC5 Expression

    • Authors: Mingzhi Zhang, Xinxin Yan, Peihao Wen, Wenkun Bai, Qingyu Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      CircRNAs participate in the pathogenesis of a variety of cancers. Previous studies showed that baculoviral IAP repeat containing 5 (BIRC5) can promote tumor progression. But, the mechanisms by which circRNAs regulate BIRC5 expression in hepatocellular carcinoma (HCC) remain unknown. The clinical prognosis of BIRC5 or miR-497-5p expression in patients with HCC was assessed by TCGA RNA-seq dataset. hsa_circ_0026939 (circANKRD52) or BIRC5 was identified to bind with miR-497-5p by luciferase gene report, RIP and circRIP assays. MTT, colony formation, Transwell assays and a xenograft tumor model were used to estimate the role of miR-497-5p or circANKRD52 in HCC cells. As a result, we found that elevated expression of BIRC5 or decreased expression of miR-497-5p was linked to poor survival in HCC. Restored expression of miR-497-5p repressed cell proliferation, colony formation and invasiveness by targeting BIRC5, but its inhibitor showed the opposite results. Furthermore, circANKRD52 possessed a tumor-promoting effect by acting as a sponge of miR-497-5p and thereby upregulated BIRC5 in HCC cells. In conclusion, our findings demonstrated that circANKRD52 enhances the tumorigenesis of HCC by sponging miR-497-5p and upregulating BIRC5 expression.
      Citation: Cell Transplantation
      PubDate: 2021-04-13T06:27:04Z
      DOI: 10.1177/09636897211008874
      Issue No: Vol. 30 (2021)
  • Surviving the Rookie Virus, Severe Acute Respiratory Syndrome Coronavirus
           2 (SARS-CoV2): The Immunopathology of a SARS-CoV2 Infection

    • Authors: Sheng Feng Tsai, Kang-Yun Lu, Hong-Meng Chuang, Ching-Ann Liu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Until July 29th, the number of confirmed coronavirus (COVID-19) cases worldwide has risen to over 16 million, within which 655 k deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) emerges as the 11th global pandemic disease, showing the highest infectivity and lowest infection fatality rate. In this review, we compare the immunopathology among SARS-CoV, Middle East respiratory syndrome coronavirus, and SARS-CoV2. SARS-CoV2 is similar to SARS-CoV; it can cause lymphocytopenia and a rising granulocyte count. Here we point out the human body and concentrated society make for an excellent incubator for virus evolution. Most research energies put into developing the SARS-CoV2 vaccine are trying to block virus infection. Sixty-five percent of severe patients die with multiple organ failure, inflammation, and cytokine storm, which indicates that the patient’s immune system maintains functionality. Finding a way to trigger the specific T cell subset and plasmablast in our body is the best shot to get away with SARS-CoV2.
      Citation: Cell Transplantation
      PubDate: 2021-04-12T07:10:49Z
      DOI: 10.1177/0963689721993769
      Issue No: Vol. 30 (2021)
  • RAI14 Regulated by circNFATC3/miR-23b-3p axis Facilitates Cell Growth and
           Invasion in Gastric Cancer

    • Authors: XinXin Yan, MingZhi Zhang, BingBing Li, Xia Ji, HongJin Wu, QingYu Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Circular RNAs (circRNAs) have been proved to act crucial roles in multiple malignancies including gastric cancer (GC). Retinoic acid induced 14 (RAI14) acts as an oncogene in human cancers, but the underlying mechanisms by which RAI14 is regulated by circRNA/miRNA axis remain elusive. The clinical value of RAI14, miR-23b-3p and circNFATC3 was estimated by The Cancer Genome Atlas and fluorescence in situ hybridization. The interplay between miR-23b-3p and RAI14 or circNFATC3 was determined by qRT-PCR, Western blot, luciferase gene report and RIP assays. Biological function assays and a subcutaneous xenograft model were executed to unveil the role of circNFATC3/miR-23b-3p/RAI14 axis in GC cells. As a consequence, upregulation of RAI14 and circNFATC3 or downregulation of miR-23b-3p was associated with poor prognosis in patients with GC. Restored miR-23b-3p depressed cell proliferation, colony formation, and cell invasion by targeting RAI14, whereas RAI14 facilitated cell progression and reversed the anti-tumor effects of miR-23b-3p in GC cells. Then, circNFATC3 had a co-localization with miR-23b-3p in the cytoplasm in GC tissue cells and could act as a sponge of miR-23b-3p in GC cell line. Silencing of circNFATC3 inhibited cell growth and in vivo tumorigenesis by upregulating miR-23b-3p and downregulating RAI14. In conclusion, our findings indicated that RAI14 facilitated cell growth and invasion and was regulated by circNFATC3/miR-23b-3p axis in GC.
      Citation: Cell Transplantation
      PubDate: 2021-04-12T07:10:48Z
      DOI: 10.1177/09636897211007055
      Issue No: Vol. 30 (2021)
  • PRMT5 Promotes EMT Through Regulating Akt Activity in Human Lung Cancer

    • Authors: Jianhao Huang, Yonghua Zheng, Xiao Zheng, Bao Qian, Qi Yin, Jingjing Lu, Han Lei
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The type II protein arginine methyltransferase 5 (PRMT5) has been engaged in various human cancer development and progression types. Nevertheless, few studies uncover the biological functions of PRMT5 in the epithelial-mesenchymal transition (EMT) of human lung cancer cells, and the associated molecular mechanisms and signaling cascades are entirely unknown. Here, we show that PRMT5 is the ectopic expression in human lung cancer tissues and cell lines. Further study reveals that silencing PRMT5 by lentivirus-mediated shRNA or blocking of PRMT5 by specific inhibitor GSK591 attenuates the expression levels of EMT-related markers in vivo, using the xenograft mouse model. Moreover, our results show that down-regulation of PRMT5 impairs EGFR/Akt signaling cascades in human lung cancer cells, whereas re-expression of PRMT5 recovers those changes, suggesting that PRMT5 regulates EMT probably through EGFR/Akt signaling axis. Altogether, our results demonstrate that PRMT5 serves as a critical oncogenic regulator and promotes EMT in human lung cancer cells. More importantly, our findings also suggest that PRMT5 may be a potential therapeutic candidate for the treatment of human lung cancer.
      Citation: Cell Transplantation
      PubDate: 2021-04-08T01:37:57Z
      DOI: 10.1177/09636897211001772
      Issue No: Vol. 30 (2021)
  • LncRNA MNX1-AS1 Contributes to Laryngeal Squamous Cell Carcinoma Growth
           and Migration by Regulating mir-744-5p/bcl9/β-Catenin Axis

    • Authors: Bingliang Ma, Gang Ren, Jue Xu, Chenyi Yin, Yuye Shi
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are involved in the progression of laryngeal squamous cell carcinoma (LSCC). Here, we aimed to disclose the role of MNX1-AS1 in LSCC progression, and explore whether MNX1-AS1 participates in LSCC progression via targeting miR-744-5p to active BCL9/β-catenin signaling. Sixty-five human LSCC tissues and the paracancerous normal tissues were recruited to determine the levels of MNX1-AS1, miR-744-5p and BCL9 using qRT-PCR. The interaction of miR-744-5p and MNX1-AS1/BCL9 was determined by using the RNA immunoprecipitation (RIP) assay and/or luciferase gene reporter assay. Cell viability, in vivo tumor formation, invasion and migration abilities were detected by MTT, Xenograft models and Transwell assays. MNX1-AS1 level was increased significantly in human LSCC tissues as compared with the normal tissues, which showed a positive correlation with BCL9 level while a negative correlation with miR-744-5p level. High level of MNX1-AS1 predicted a poor prognosis and an advanced clinical process in LSCC patients. miR-744-5p targeted upregulation weakened the luciferase activity of MNX1-AS1 and /BCL9, and downregulated their expression levels-wt, while showed no effect when the binding sites were mutated. Knockdown of MNX1-AS1 markedly weakened cell viability, migration, and invasion abilities, while BCL9 overexpression abolished these tendencies. In addition, MNX1-AS1 downregulation induced decreases in tumor volumes and weights in vivo, accompanied by reductions in BCL9, Ki-67 and β-catenin expression and an increase in miR-744-5p expression. Collectively, this study reveals that MNX1-AS1 contributes to cell growth and migration by regulating miR-744-5p/BCL9/β-catenin axis in LSCC.
      Citation: Cell Transplantation
      PubDate: 2021-04-06T11:41:37Z
      DOI: 10.1177/09636897211005682
      Issue No: Vol. 30 (2021)
  • Identification of an Immune Gene Signature Based on Tumor Microenvironment
           Characteristics in Colon Adenocarcinoma

    • Authors: Ying Chen, Jia Zhao
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Tumor microenvironment (TME) changes are related to the occurrence and development of colon adenocarcinoma (COAD). This study aimed to analyze the characteristics of the immune microenvironment in CC, as well as the microenvironment’s relationship with the clinical features of CC. Based on The Cancer Genome Atlas (TCGA) and GSE39582 cohorts, the scores of 22 tumor infiltrating lymphocytes (TILs) were calculated using CIBERSORT. ConsensusClusterPlus was used for unsupervised clustering. Three TME subtypes (TMEC1, TMEC2, and TME3) were identified based on TIL scores. TMEC2 was associated with the worst prognosis. Random forest, k-means clustering, and principal component analysis were used to construct the TME score risk signature. The median TME score was used to divide the samples into high- and low-risk groups. The prognoses of the patients with high TME scores were worse than those of the patients with low TME scores. A high TME score was an independent prognostic risk factor for patients with colon cancer. The Gene Set Enrichment Analysis (GSEA) results showed that those with high TME scores were enriched in FOCAL_ADHESION, ECM_RECEPTOR_INTERACTION, and PATHWAYS_IN_CANCER. Our findings will provide a new strategy for immunotherapy in patients with CC.
      Citation: Cell Transplantation
      PubDate: 2021-03-31T11:27:08Z
      DOI: 10.1177/09636897211001314
      Issue No: Vol. 30 (2021)
  • Predictive Value of Degranulating Factors of Neutrophils in Massive
           Cerebral Infarction

    • Authors: Yuyou Huang, Fangfang Li, Zhongyun Chen, Weibi Chen, Linlin Fan, Yangmin Zheng, Ziping Han, Lingzhi Li, Yumin Luo, Yan Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Massive cerebral infarction (MCI) is a life-threatening disease and may lead to cerebral herniation. Neutrophil degranulation contributes to ischemic injury in the early stage. To investigate whether neutrophil degranulating factors can predict cerebral herniation and the long-term prognosis of patients with MCI and to investigate the relationship between neutrophil degranulation and blood brain barrier (BBB) damage. In this case-control study of 14 MCI patients, we divided the patients into a cerebral hernia group and no cerebral hernia group according to whether they developed cerebral herniation within 5 days. The prognosis of MCI patients was assessed using the Modified Rankin Scale (mRS) score at 6 months, which was the primary end point. The composition of white blood cells (WBC) and degranulating factors for neutrophils in the plasma of MCI patients was determined on days 2 and 4. Baseline characteristics were comparable in both groups. The neurological functional scores and long-term prognosis showed no difference between patients with or without cerebral herniation, while the mortality rate of the cerebral hernia group in the short term was higher (P < 0.05). The WBC count, neutrophil to lymphocyte ratio (NLR) and plasma myeloperoxidase (MPO) levels of patients with cerebral hernia were significantly higher than those of patients without cerebral hernia (all P < 0.05). MPO is a better predictor of cerebral herniation, and the NLR showed superior predictive value in the prognosis of MCI patients. neutrophil degranulation may play an important role in malignant cerebral hernia during MCI. These data suggest that, MPO and the NLR might be predictive factors for cerebral herniation and the prognosis of MCI patients.
      Citation: Cell Transplantation
      PubDate: 2021-03-31T11:27:07Z
      DOI: 10.1177/09636897211004089
      Issue No: Vol. 30 (2021)
  • Telocytes Enhances M1 Differentiation and Phagocytosis While Inhibits
           Mitochondria-Mediated Apoptosis Via Activation of NF-κB in Macrophages

    • Authors: Yue-Lin Huang, Fei-Lei Zhang, Xue-Ling Tang, Xiao-Jun Yang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Telocytes (TCs), which are a recently discovered interstitial cell type present in various organs and tissues, perform multiple biological functions and participate in extensive crosstalk with neighboring cells. Endometriosis (EMs) is a gynecological disease characterized by the presence of viable endometrial debris and impaired macrophage phagocytosis in the peritoneal environment. Here, CD34/vimentin-positive TCs were co-cultured with RAW264.7 cells in vitro. M1/M2 differentiation-related markers were detected; phagocytosis, energy metabolism, proliferation, apoptosis, and pathway mechanisms were studied; and the mitochondrial membrane potential (ΔΨm) was measured. Furthermore, in an EMs mouse model, the differentiation of macrophages in response to treatment with TC-conditioned medium (TCM) in vivo was studied. The results showed that upon in vitro co-culture with TCM, RAW264.7 cells differentiated more toward the M1 phenotype with enhancement of phagocytosis, increase in energy metabolism and proliferation owing to reduced the loss of ΔΨm, and suppression of dexamethasone-induced apoptosis. Further, along with the activation of NF-κB, Bcl-2 and Bcl-xl, the expression of Bax, cleaved-caspase9, and cleaved-caspase3 reduced in RAW264.7 cells. In addition, the M1 subtype was found to be the dominant phenotype among tissue and peritoneal macrophages in the EMs model subjected to in vivo TCM treatment. In conclusion, TCs enhanced M1 differentiation and phagocytosis while inhibiting apoptosis via the activation of NF-κB in macrophages, which potentially inhibited the onset of EMs. Our findings provide a potential research target and the scope for developing a promising therapeutic strategy for EMs.
      Citation: Cell Transplantation
      PubDate: 2021-03-31T11:27:06Z
      DOI: 10.1177/09636897211002762
      Issue No: Vol. 30 (2021)
  • Infusion of Kupffer Cells Expanded in Vitro Ameliorated Liver Fibrosis in
           a Murine Model of Liver Injury

    • Authors: Weina Li, Fei He
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Transfer of exogenous macrophages represents an alternative technique to treat liver fibrosis. At present, bone marrow-derived monocytes and stem cells are the main sources for exogenous macrophages. Kupffer cells (KCs) are the resident macrophages in the liver and play a critical role in the liver homeostasis and diseases. It is unclear whether infusion of KCs can treat liver fibrosis. In this study, we observed that granulocyte-macrophage colony stimulating factor (GM-CSF) could improve the purity of cultured KCs and significantly up-regulate the expression of Cluster of Differentiation 11b (CD11b). The most important point is that GM-CSF could significantly promote the proliferation of KCs in vitro. KCs expanded in vitro still had the potential of M1/M2 polarization and phagocytosis. Furthermore, infusion of these KCs could ameliorate liver fibrosis induced by carbon tetrachloride (CCl4) in mice. Together, our results suggest that KCs are likely to be another source for macrophage therapy.
      Citation: Cell Transplantation
      PubDate: 2021-03-31T07:39:17Z
      DOI: 10.1177/09636897211004090
      Issue No: Vol. 30 (2021)
  • Protective Effects of Reduced Glutathione and Ulinastatin on
           Xeno-transplanted Human Ovarian Tissue Against Ischemia and Reperfusion

    • Authors: Yubin Li, Yue Hu, Shunye Zhu, Ying Tuo, Bin Cai, Tengfei Long, Wen Zhao, Xiaoxin Ye, XiaoFang Lu, Lingli Long
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Recently, transplantation of cryopreserved ovarian tissue is the method for fertility preservation for oncologic and nononcologic reasons. The main challenge of ovarian cryopreservation followed by transplantation is that ischemia reperfusion injury (IRI) induced the loss of follicles. The aim of this study was to evaluate the effects of glutathione (GSH), ulinastatin (UTI) or both (GSH+UTI) on preventing ischemia reperfusion-induced follicles depletion in ovarian grafts.Ovarian fragments were collected from 20 women aged 29±6 years. Frozen-thawed human ovarian tissue was xenografted into SCID mice, at the same time GSH, UTI and GSH+UTI was administrated respectively. The ovarian grafts were collected at the 1st, 3rd, 7th, 14th, 28th, 56th, and 85th day after xenotransplantation. Follicle survival rate was measured by H&E staining and Live/Dead staining. Angiogenic activity and macrophage recruitment was evidenced by immunohistochemical staining. The oxidative stress and inflammatory cytokines in human ovarian xenografts were measured by real-time PCR. The results indicated that after the treatments of GSH, UTI and GSH+UTI in the hosts, follicular survival in ovarian grafts were improved. The level of VEGF, CD31, and antioxidant enzymes superoxide dismutase 1 and superoxide dismutase 2 in ovarian grafts were increased. Accumulation of macrophages, level of IL6 and TNF-α, as well as malondialdehyde was decreased in ovarian grafts from treated groups. In conclusion, administration of GSH, UTI and GSH+UTI decreased the depletion of follicles in human grafts post-transplantation by inhibiting IRI-induced antiangiogenesis, oxidative stress and inflammation.
      Citation: Cell Transplantation
      PubDate: 2021-03-30T06:30:21Z
      DOI: 10.1177/0963689721997151
      Issue No: Vol. 30 (2021)
  • Corrigendum

    • Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.

      Citation: Cell Transplantation
      PubDate: 2021-03-25T05:24:18Z
      DOI: 10.1177/0963689721992674
      Issue No: Vol. 30 (2021)
  • Identification of Differential Expression Cytokines in Hemolysis, Elevated
           Liver Enzymes, and Low Platelet Syndrome by Proteome Microarray Analysis
           and Further Verification

    • Authors: Suya Kang, Liping Zhou, Yun Wang, Hui Li, Hong Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      To screen the differential expression cytokines (DECs) in hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome, establish its differential cytokines spectra, and provide the clues for its diagnosis and pathogenic mechanism researches. Sera from four HELLP syndrome patients and four healthy controls were detected by proteome microarray. Then the analysis of Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein–protein interaction (PPI) network were performed and possible hub proteins were selected out, further verified by Enzyme Linked Immunosorbent Assay (ELISA) in sera from 21 HELLP syndrome patients and 21 healthy controls. Thirty DECs were defined according to P-value and fold change between HELLP group and control group. GO enrichment analysis showed that DECs were mainly involved in the regulation of inflammatory response and have relationship to growth factor binding, transmembrane receptor protein kinase, and cytokine receptor activity. Seven possible hub proteins were defined by PPI analysis, including IGFBP-3/Follistatin-like 1/FLRG/Fetuin A and MMP-13/Thrombospondin-5/Aggrecan. ELISA showed higher serum levels of Fetuin A/IGFBP-3/FLGR/MMP-13/Thrombospondin-5 in HELLP group than those in controls, while the levels of Follistatin-like 1 and Aggrecan were lower in HELLP patients (all P < 0.05 or
      Citation: Cell Transplantation
      PubDate: 2021-03-24T07:35:34Z
      DOI: 10.1177/0963689720975398
      Issue No: Vol. 30 (2021)
  • Cryopreservation: An Overview of Principles and Cell-Specific

    • Authors: David Whaley, Kimia Damyar, Rafal P. Witek, Alan Mendoza, Michael Alexander, Jonathan RT Lakey
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The origins of low-temperature tissue storage research date back to the late 1800s. Over half a century later, osmotic stress was revealed to be a main contributor to cell death during cryopreservation. Consequently, the addition of cryoprotective agents (CPAs) such as dimethyl sulfoxide (DMSO), glycerol (GLY), ethylene glycol (EG), or propylene glycol (PG), although toxic to cells at high concentrations, was identified as a necessary step to protect against rampant cell death during cryopreservation. In addition to osmotic stress, cooling and thawing rates were also shown to have significant influence on cell survival during low temperature storage. In general, successful low-temperature cell preservation consists of the addition of a CPA (commonly 10% DMSO), alone or in combination with additional permeating or non-permeating agents, cooling rates of approximately 1ºC/min, and storage in either liquid or vapor phase nitrogen. In addition to general considerations, cell-specific recommendations for hepatocytes, pancreatic islets, sperm, oocytes, and stem cells should be observed to maximize yields. For example, rapid cooling is associated with better cryopreservation outcomes for oocytes, pancreatic islets, and embryonic stem cells while slow cooling is recommended for cryopreservation of hepatocytes, hematopoietic stem cells, and mesenchymal stem cells. Yields can be further maximized by implementing additional pre-cryo steps such as: pre-incubation with glucose and anti-oxidants, alginate encapsulation, and selecting cells within an optimal age range and functional ability. Finally, viability and functional assays are critical steps in determining the quality of the cells post-thaw and improving the efficiency of the current cryopreservation methods.
      Citation: Cell Transplantation
      PubDate: 2021-03-24T07:35:32Z
      DOI: 10.1177/0963689721999617
      Issue No: Vol. 30 (2021)
  • Myeloablative Haploidentical Transplant as an Alternative to Matched
           Sibling Transplant for Peripheral T-Cell Lymphomas

    • Authors: Gu Zhenyang, Li Nainong, Wu Xiaoxiong, Wang Maihong, Fu Xiaorui, Wang Zhao, Ren Hanyun, Li Yuhang, Li Xiaofan, Wu Yamei, Liu Yao, Zhang Mingzhi, Wang Yini, Liu Daihong, Dong Yujun, Hu Liangding, Huang Wenrong
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The number of HLA-haploidentical allogeneic hematopoietic stem-cell transplantation (Haplo-HSCT) is increasing. Comparative studies about Haplo-HSCT versus allo-HSCT with HLA-matched sibling donors (MSD-HSCT) have been tried in leukemias and B-cell lymphomas. Few studies were reported in Peripheral T-cell lymphomas (PTCLs). We performed a multicenter retrospective study about 52 patients with PTCLs undergoing Haplo-HSCT (n = 20) or MSD-HSCT (n = 32). All Haplo-HSCT recipients received antithymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis. The median follow-up for all survivors was 38 months. The 100-day cumulative incidence of grade II to IV acute GVHD was similar (19% in the MSD-HSCT group versus 28% in the Haplo-HSCT group, P = 0.52). The 2-year cumulative incidence of chronic GVHD (limited and extensive) after Haplo-HSCT (30%) was also similar with that in the MSD-HSCT group (50%, P = 0.15). The 3-year relapse rates (33% vs 27%, P = 0.84) and non-relapse mortality (21% vs 22%, P = 0.78) did not differ between these two groups. There were also no differences in 3-year overall survival (OS) (48% vs 50%, P = 0.78) and progression-free survival (47% vs 51%, P = 0.95) between these two groups. On multivariate analysis, prognostic index for T-cell lymphoma (PIT) score (higher than 1: hazard ratio [HR], 4.0; P = 0.003) and disease status (stable or progression disease before HSCT: HR, 2.8; P = 0.03) were independent variables associated with worse OS. We concluded that ATG-based haplo-HSCT platform could work as an alternative to MSD-HSCT for patients with PTCLs.
      Citation: Cell Transplantation
      PubDate: 2021-03-22T03:00:18Z
      DOI: 10.1177/0963689721999615
      Issue No: Vol. 30 (2021)
  • Endoderm and Hepatic Progenitor Cells Engraft in the Quiescent Liver
           Concurrent with Intrinsically Activated Epithelial-to-Mesenchymal

    • Authors: W. Samuel Fagg, Naiyou Liu, Igor Patrikeev, Omar A. Saldarriaga, Massoud Motamedi, Vsevolod L. Popov, Heather L. Stevenson, Jeffrey H. Fair
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Stem cell transplantation to the liver is a promising therapeutic strategy for a variety of disorders. Hepatocyte transplantation has short-term efficacy but can be problematic due to portal hypertension, inflammation, and sinusoidal thrombosis. We have previously transplanted small mouse endoderm progenitor (EP) cells to successfully reverse a murine model of hemophilia B, and labeling these cells with iron nanoparticles renders them responsive to magnetic fields, which can be used to enhance engraftment. The mechanisms mediating progenitor cell migration from the sinusoidal space to the hepatocyte compartment are unknown. Here we find human EP and hepatic progenitor (HP) cells can be produced from human embryonic stem cells with high efficiency, and they also readily uptake iron nanoparticles. This provides a simple manner through which one can readily identify transplanted cells in vivo using electron microscopy, shortly after delivery. High resolution imaging shows progenitor cell morphologies consistent with epithelial-to-mesenchymal transition (EMT) mediating invasion into the hepatic parenchyma. This occurs in as little as 3 h, which is considerably faster than observed when hepatocytes are transplanted. We confirmed activated EMT in transplanted cells in vitro, as well as in vivo 24 h after transplantation. We conclude that EMT naturally occurs concurrent with EP and HP cell engraftment, which may mediate the rate, safety, and efficacy of early cell engraftment in the undamaged quiescent liver.
      Citation: Cell Transplantation
      PubDate: 2021-03-04T07:20:00Z
      DOI: 10.1177/0963689721993780
      Issue No: Vol. 30 (2021)
  • Deciphering the Emerging Roles of Adipocytes and Adipose-Derived Stem
           Cells in Fat Transplantation

    • Authors: Yi Yi, Weijie Hu, Chongru Zhao, Min Wu, Hong Zeng, Mingchen Xiong, Wenchang Lv, Yiping Wu, Qi Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Autologous fat transplantation is widely regarded as an increasingly popular method for augmentation or reshaping applications in soft tissue defects. Although the fat transplantation is of simple applicability, low donor site morbidity and excellent biocompatibility, the clinical unpredictability and high resorption rates of the fat grafts remain an inevitable problem. In the sites of fat transplantation, the most essential components are the adipocyte and adipose-derived stem cells (ADSCs). The survival of adipocytes is the direct factor determining fat retention. The efficacy of fat transplantation is reduced by fat absorption and fibrosis due to the inadequate blood flow, adipocyte apoptosis and fat necrosis. ADSCs, a heterogeneous mixture of cells in adipose tissue, are closely related to tissue survival. ADSCs exhibit the ability of multilineage differentiation and remarkable paracrine activity, which is crucial for graft survival. This article will review the recent existing research on the mechanisms of adipocytes and ADSCs in fat transplantation, especially including adipocyte apoptosis, mature adipocyte dedifferentiation, adipocyte browning, ADSCs adipogenic differentiation and ADSCs angiogenesis. The in-depth understanding of the survival mechanism will be extremely valuable for achieving the desired filling effects.
      Citation: Cell Transplantation
      PubDate: 2021-03-02T04:23:28Z
      DOI: 10.1177/0963689721997799
      Issue No: Vol. 30 (2021)
  • Mesenchymal Stromal Cell-Based Therapy: A Promising Approach for Severe

    • Authors: Jing Xiong, Long Chen, Li Zhang, Lei Bao, Yuan Shi
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      During the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many critically ill patients died of severe pneumonia, acute respiratory distress syndrome (ARDS), or multiple organ dysfunction syndrome. To date, no specific treatments have been proven to be effective for coronavirus disease 2019 (COVID-19). In the animal models and clinical applications, mesenchymal stromal/stem cells (MSCs) have been shown safety and efficacy for the treatment of respiratory virus infection through their abilities of differentiation and immunomodulation. Besides, possessing several advantages of MSC-derived extracellular vesicles (EVs) over MSCs, EV-based therapy also holds potential therapeutic effects in respiratory virus infection. In this review, we summarized the basic characteristics and mechanisms of COVID-19 and MSCs, outlined some preclinical and clinical studies of MSCs or MSC-EVs for respiratory virus infection such as influenza virus and SARS-CoV-2, shed light on the common problems that we should overcome to translate MSC therapy into clinical application, and discussed some safe issues related to the use of MSCs.
      Citation: Cell Transplantation
      PubDate: 2021-03-02T04:20:50Z
      DOI: 10.1177/0963689721995455
      Issue No: Vol. 30 (2021)
  • Tumor Suppressor Gene XEDAR Promotes Differentiation and Suppresses
           Proliferation and Migration of Gastric Cancer Cells Through Upregulating
           the RELA/LXRα Axis and Deactivating the Wnt/β-Catenin Pathway

    • Authors: Xinwu Zhang, Di Zhang, Xiaoli Sun, Shunle Li, Yun Sun, Hongjun Zhai
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      X-linked ectodermal dysplasia receptor (XEDAR) is a new member of the tumor necrosis factor receptor (TNFR) family that induces cell death. The purpose of this study is to determine the tumor-suppressive potential of XEDAR in the development and differentiation of gastric cancer (GC). XEDAR levels were analyzed in human GC tissues and adjacent normal tissues by immunohistochemistry (IHC), quantitative real-time reverse transcription PCR (RT-qPCR), and Western blot analysis. We found that XEDAR expression was significantly downregulated in GC tissues and further decreased in low differentiated GC tissues. Overexpression of XEDAR in MKN45 and MGC803 cells suppressed the ability of cell proliferation and migration, whereas silencing XEDAR showed the opposite effect. Additionally, XEDAR silencing resulted in the upregulation of the differentiation molecular markers β-catenin, CD44 and Cyclin D1 at the protein levels, whereas XEDAR overexpression showed the opposite effect. Notably, XEDAR positively regulated the expression of liver X receptor alpha (LXRα) through upregulating the RELA gene that was characterized as a transcription factor of LXRα in this study. Inhibition of LXRα by GSK2033 or activation of the Wnt/β-catenin pathway by Wnt agonist 1 impaired the effect of XEDAR overexpression on differentiation of MKN45 cells. Moreover, inhibition of RELA mediated by siRNA could promote cell proliferation/migration and rescue the effect of XEDAR overexpression on cell behaviors and expression of genes. Subsequently, overexpression of XEDAR suppressed the growth of GC cells in vivo. Taken together, our findings showed that XEDAR could promote differentiation and suppress proliferation and invasion of GC cells.
      Citation: Cell Transplantation
      PubDate: 2021-02-27T07:43:28Z
      DOI: 10.1177/0963689721996346
      Issue No: Vol. 30 (2021)
  • miR-22 Host Gene Enhances Nuclear Factor-kappa B Activation to Aggravate
           Hypoxia-induced Injury in AC16 Cardiomyocytes

    • Authors: Xu Yan, Jinlan Hou
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Myocardial infarction (MI) is a severe life-threatening disease caused by acute and persistent ischemia and hypoxia and eventually leads to heart failure and sudden death. Long noncoding RNAs (lncRNAs) play significant roles in the pathology, diagnosis, and development of various cardiovascular diseases, including MI. This study aimed to explore the effect and molecular mechanism of lncRNA miR-22 host gene (MIR22HG) on hypoxia-induced injury in AC16 cardiomyocytes. The expression of MIR22HG and miR-24 in hypoxia-treated AC16 cardiomyocytes was detected by quantitative real-time polymerase chain reaction. Cell viability, lactate dehydrogenase release, levels of aspartate aminotransferase (AST) and creatine kinase-MB (CK-MB), and apoptosis were detected by Cell Counting Kit-8, lactate dehydrogenase (LDH) release assay, commercial enzyme-linked immune sorbent assay kits, and flow cytometry analysis, respectively. The protein levels of nuclear factor-kappa B (NF-κB) p65 and cytoplasmic inhibitor of kappa B alpha (IκBα) and phosphorylated IκBα were detected by western blot. Results showed that hypoxia treatment decreased viability and increased MIR22HG expression in AC16 cardiomyocytes. MIR22HG overexpression aggravated hypoxia-induced viability reduction, leakage of myocardial injury markers LDH, AST, and CK-MB, and apoptosis in AC16 cardiomyocytes, while MIR22HG knockdown elicited the reverse effects. MIR22HG overexpression enhanced NF-κB activation in hypoxia-treated AC16 cardiomyocytes. Inhibition of NF-κB pathway impaired the effects of MIR22HG overexpression on hypoxia-induced injury in AC16 cardiomyocytes. Moreover, MIR22HG knockdown inhibited the NF-κB pathway by upregulating miR-24 in AC16 cardiomyocytes. Inhibition of miR-24 resisted the effects of MIR22HG silencing on hypoxia-induced injury in AC16 cardiomyocytes. In conclusion, MIR22HG overexpression aggravated hypoxia-induced injury in AC16 cardiomyocytes via enhancing NF-κB activation by targeting miR-24.
      Citation: Cell Transplantation
      PubDate: 2021-02-26T07:18:54Z
      DOI: 10.1177/0963689721990323
      Issue No: Vol. 30 (2021)
  • Successful Treatment of Pediatric Refractory Burkitt Lymphoma PTLD after
           Liver Transplantation using Anti-CD19 Chimeric Antigen Receptor T-Cell

    • Authors: Tianyi Wang, Mingxuan Feng, Chengjuan Luo, Xinyu Wan, Ci Pan, Jingyan Tang, Feng Xue, Minzhi Yin, Dongqing Lu, Qiang Xia, Benshang Li, Jing Chen
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      In the immunocompromised setting, recipients of solid-organ or hematopoietic stem-cell transplants carry an increased risk of post-transplant lymphoproliferative disorder (PTLD). Burkitt lymphoma (BL) PTLD is a rare form of monomorphic B-cell PTLD, which lacks a standard best treatment. Here, we report the successful treatment of refractory BL-PTLD with autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. A male patient was diagnosed with BL-PTLD, with an increasing Epstein-Barr virus (EBV) viral load, at 21 months after undergoing living liver transplantation from his mother due to neonatal biliary atresia. After 10 cycles rituximab +/− intensive chemotherapy and surgical tumor resection, the tumors significantly advanced. Next-generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded tumor tissue, revealing one mutation in exon 5, TP53: p.A159 V, which may be associated with chemo-resistance. Thus, treatment was started with autologous anti-CD19 CAR T-cell therapy. We administered 9.0 × 106/kg autologous anti-CD19 CAR T-cells, after conditioning with cyclophosphamide and fludarabine. Unexpectedly, the patient experienced only mild (Grade II) cytokine release syndrome (CRS) without neurotoxicity. Finally, he went into complete remission (CR), and has achieved 16-month event-free survival to date. In addition, liver function has remained stably within the normal range without any immunosuppressive therapy. The literature includes only five previously reported BL cases treated with CAR T-cell therapy. In conclusion, the present case suggests that autologous anti-CD19 CAR T-cell therapy may represent a new therapeutic option for some cases of refractory BL-PTLD.Clinical trial number: ChiCTR2000032211.
      Citation: Cell Transplantation
      PubDate: 2021-02-26T07:18:54Z
      DOI: 10.1177/0963689721996649
      Issue No: Vol. 30 (2021)
  • Feasibility of Umbilical Cord Blood Collection in Neonates at Risk of
           Brain Damage—A Step Toward Autologous Cell Therapy for a High-risk

    • Authors: Angela Segler, Thorsten Braun, Hendrik Stefan Fischer, Ricarda Dukatz, Claire-Rachel Weiss, Alexander Schwickert, Carsten Jäger, Christoph Bührer, Wolfgang Henrich
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Evidence for umbilical cord blood (UCB) cell therapies as a potential intervention for neurological diseases is emerging. To date, most existing trials worked with allogenic cells, as the collection of autologous UCB from high-risk patients is challenging. In obstetric emergencies the collection cannot be planned. In preterm infants, late cord clamping and anatomic conditions may reduce the availability. The aim of the present study was to assess the feasibility of UCB collection in neonates at increased risk of brain damage. Infants from four high-risk groups were included: newborns with perinatal hypoxemia, gestational age (GA) ≤30 + 0 weeks and/or birthweight
      Citation: Cell Transplantation
      PubDate: 2021-02-26T07:18:52Z
      DOI: 10.1177/0963689721992065
      Issue No: Vol. 30 (2021)
  • Development and Clinical Validation of a Seven-Gene Prognostic Signature
           Based on Multiple Machine Learning Algorithms in Kidney Cancer

    • Authors: Mi Tian, Tao Wang, Peng Wang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      About a third of patients with kidney cancer experience recurrence or cancer-related progression. Clinically, kidney cancer prognoses may be quite different, even in patients with kidney cancer at the same clinical stage. Therefore, there is an urgent need to screen for kidney cancer prognosis biomarkers. Differentially expressed genes (DEGs) were identified using kidney cancer RNA sequencing data from the Gene Expression Omnibus (GEO) database. Biomarkers were screened using random forest (RF) and support vector machine (SVM) models, and a multigene signature was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. Univariate and multivariate Cox regression analyses were performed to explore the relationships between clinical features and prognosis. Finally, the reliability and clinical applicability of the model were validated, and relationships with biological pathways were identified. Western blots were also performed to evaluate gene expression. A total of 50 DEGs were obtained by intersecting the RF and SVM models. A seven-gene signature (RNASET2, EZH2, FXYD5, KIF18A, NAT8, CDCA7, and WNT7B) was constructed by LASSO regression. Univariate and multivariate Cox regression analyses showed that the seven-gene signature was an independent prognostic factor for kidney cancer. Finally, a predictive nomogram was established in The Cancer Genome Atlas (TCGA) cohort and validated internally. In tumor tissue, RNASET2 and FXYD5 were highly expressed and NAT8 was lowly expressed at the protein and transcription levels. This model could complement the clinicopathological characteristics of kidney cancer and promote the personalized management of patients with kidney cancer.
      Citation: Cell Transplantation
      PubDate: 2021-02-25T07:36:53Z
      DOI: 10.1177/0963689720969176
      Issue No: Vol. 30 (2021)
  • Safety of Intraovarian Injection of Human Mesenchymal Stem Cells in a
           Premature Ovarian Insufficiency Mouse Model

    • Authors: Hang-Soo Park, Rishi Man Chugh, Amro Elsharoud, Mara Ulin, Sahar Esfandyari, Alshimaa Aboalsoud, Lale Bakir, Ayman Al-Hendy
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Primary ovarian insufficiency (POI), a condition in which there is a loss of ovarian function before the age of 40 years, leads to amenorrhea and infertility. In our previously published studies, we demonstrated recovery of POI, correction of serum sex hormone levels, increase in the granulosa cell population, and restoration of fertility in a chemotherapy-induced POI mouse model after intraovarian transplantation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). While hBM-MSC may be a promising cell source for treatment of POI, there are few reports on the safety of stem cell-based therapy for POI. For future clinical applications, the safety of allogenic hBM-MSCs for the treatment of POI through intraovarian engraftment needs to be addressed and verified in appropriate preclinical models. In this study, we induced POI in C57/BL6 mice using chemotherapy, then treated the mice with hBM-MSCs (500,000 cells/ovary) by intraovarian injection. After hBM-MSC treatment, we analyzed the migration of engrafted cells by genomic DNA polymerase chain reaction (PCR) using a human-specific ALU repeat and by whole-body sectioning on a cryo-imaging system. We examined the possibility of transfer of human DNA from the hBM-MSCs to the resulting offspring, and compared the growth rate of offspring to that of normal mice and hBM-MSC-treated mice. We found that engrafted hBM-MSCs were detected only in mouse ovaries and did not migrate into any other major organs including the heart, lungs, and liver. Further, we found that no human DNA was transferred into the fetus. Interestingly, the engrafted cells gradually decreased in number and had mostly disappeared after 4 weeks. Our study demonstrates that intraovarian transplantation of hBM-MSCs could be a safe stem cell-based therapy to restore fertility in POI patients.
      Citation: Cell Transplantation
      PubDate: 2021-02-17T08:19:30Z
      DOI: 10.1177/0963689720988502
      Issue No: Vol. 30 (2021)
  • Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated
           Cord Blood in Pediatric Patients with Thalassemia Major

    • Authors: Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li, Sixi Liu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
      Citation: Cell Transplantation
      PubDate: 2021-02-17T08:19:29Z
      DOI: 10.1177/0963689721994808
      Issue No: Vol. 30 (2021)
  • The Immune Cell Landscape in Renal Allografts

    • Authors: Jun Lu, Yi Zhang, Jingjing Sun, Shulin Huang, Weizhen Wu, Jianming Tan
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Immune cell infiltration plays an important role in the pathophysiology of kidney grafts, but the composition of immune cells is ill-defined. Here, we aimed at evaluating the levels and composition of infiltrating immune cells in kidney grafts. We used CIBERSORT, an established algorithm, to estimate the proportions of 22 immune cell types based on gene expression profiles. We found that non-rejecting kidney grafts were characteristic with high rates of M2 macrophages and resting mast cells. The proportion of M1 macrophages and activated NK cells were increased in antibody-mediated rejection (ABMR). In T cell-mediated rejection (TCMR), a significant increase in CD8 T cell and γδT cell infiltration was observed. CD8 positive T cells were dramatically increased in mixed-ABMR/TCMR. Then, the function of ABMR and TCMR prognostic molecular biomarkers were identified. Finally, we described the gene expression of molecular markers for ABMR diagnosis was elevated and related to the ratio of monocytes and M1 macrophages in ABMR biopsies, while the expression of TCMR diagnosis markers was increased too and positively correlated with γδT cells and activated CD4 memory T cells in TCMR biopsies. Our data suggest that CIBERSORT’s deconvolution analysis of gene expression data provides valuable information on the composition of immune cells in renal allografts.
      Citation: Cell Transplantation
      PubDate: 2021-02-17T08:19:29Z
      DOI: 10.1177/0963689721995458
      Issue No: Vol. 30 (2021)
  • Circ SMARCA5 Inhibited Tumor Metastasis by Interacting with SND1 and
           Downregulating the YWHAB Gene in Cervical Cancer

    • Authors: Xia Zhang, Qing Zhang, Ke Zhang, Fang Wang, Xiaogai Qiao, Jinquan Cui
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Cervical cancer is one of the diseases that seriously endanger women’s health. Circular RNA plays an important role in regulating the occurrence and development of cervical cancer. Here, we investigated the mechanisms of circ SMARCA5 in the development of cervical cancer. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) results showed that the expression of SMARCA5 was downregulated in cervical cancer tissues and cell lines. Then we found that overexpression of SMARCA5 inhibited proliferation and invasion, but promoted apoptosis in cervical cancer cells. These were detected by Cell Counting Kit-8, Transwell, and Annexin V-fluorescein isothiocyanate/propidium iodide detection kit, respectively, and the expression of the apoptosis-related proteins was determined by western blotting. Then we predicted that SMARCA5 combined with Staphylococcal nuclease domain-containing 1 (SND1) by starBase, and verified by RNA pull-down assay. To further reveal the molecular mechanisms of SMARCA5 in the progression of cervical cancer, the interaction protein of SND1 was predicted by STRING, and the interaction was verified by co-immunoprecipitation assay. Then, the effects of SND1 or YWHAB on the development of cervical cancer were detected by the gain and loss function test, and we found that knockdown of SND1 or YWHAB reversed the effects of SMARCA5 short interfering RNA on proliferation, invasion, and apoptosis of cervical cancer cells. Overexpression of SMARCA5 inhibited cervical cancer metastasis in vivo. Our results showed that overexpression of circ SMARCA5 inhibits the binding of SND1 to YWHAB, and inhibits the proliferation and invasion, but promotes apoptosis in cervical cancer cells, thus inhibiting the metastasis of cervical cancer.
      Citation: Cell Transplantation
      PubDate: 2021-02-16T08:30:52Z
      DOI: 10.1177/0963689720983786
      Issue No: Vol. 30 (2021)
  • Kinesin Family Member C1 Increases Temozolomide Resistance of Glioblastoma
           Through Promoting DNA Damage Repair

    • Authors: Jianheng Wu, Xinjun Wang, Xiaowei Yuan, Qiao Shan, Zhen Wang, Yuehui Wu, Jingwei Xie
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Glioblastoma (GBM) is one of the most frequent primary malignant brain tumors with a poor prognosis. Unfortunately, due to the intrinsic or acquired chemoresistance of GBM cells, it easily becomes refractory disease and tumors are easy to recur. Therefore, it is critical to elucidate the molecular mechanisms underlying the chemoresistance of GBM cells to discover more efficient therapeutic treatments. Kinesin family member C1 (KIFC1) is a normal nonessential kinesin motor that affects the progression of multiple types of cancers. However, whether KIFC1 have a function in GBM is still unexplored. Here we found that KIFC1 was upregulated in human temozolomide (TMZ)-resistant GBM tissues. KIFC1 silencing is sufficient to inhibit GBM cell proliferation and amplify TMZ-induced repression of cell proliferation. Mechanistically, KIFC1 silencing contributed to DNA damage, cell cycle arrest, and apoptosis through regulating Rad51, Akt, and DNA-PKcs phosphorylation. We also noticed that KIFC1 silencing also inhibited tumor formation and increased TMZ sensitivity through regulating Ki67, Rad51, γ-H2AX, and phosphorylation of AKT in vivo. Our findings therefore confirm the involvement of KIFC1 in GBM progression and provide a novel understanding of KIFC1-Akt axis in the sensitivity of GBM to chemotherapy.
      Citation: Cell Transplantation
      PubDate: 2021-02-16T08:26:36Z
      DOI: 10.1177/0963689721991466
      Issue No: Vol. 30 (2021)
  • c-Casitas b-Lineage Lymphoma Downregulation Improves the Ability of
           Long-term Cultured Mesenchymal Stem Cells for Promoting Angiogenesis and
           Diabetic Wound Healing

    • Authors: Chengcheng Shen, Yuangang Lu, Jianghe Zhang, Yujie Li, Yiming Zhang, Dongli Fan
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The chronic wound induced by diabetes has poor efficacy and could lead to amputation. The repair function of mesenchymal stem cells (MSCs) impaired after long-term culture in vitro. Studies have shown that the proto-oncogene c-Casitas b-lineage lymphoma (c-Cbl) can regulate receptor- and non-receptor tyrosine kinase, which was also involved in the angiogenesis process. This study aimed to explore the regulative effect of c-Cbl on the proangiogenic functions of long-term cultured MSCs and evaluate its pro-healing effect on diabetic wounds. In this study, the c-Cbl level was downregulated by locked nucleic acid–modified antisense oligonucleotide gapmers (LNA Gapmers). We detected the effect of c-Cbl downregulation on long-term cultured MSCs in terms of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal, cellular proliferation, senescence, migration, and angiogenic factors paracrine activity in vitro. In vivo, we observed the pro-healing effect of long-term cultured MSCs, with or without c-Cbl downregulation, on the diabetic wound. We found that the phosphorylation level of c-Cbl increased and that of Akt decreased in passage 10 (P10) MSCs compared with passage 3 (P3) MSCs (P < 0.05). Additionally, the proliferation, paracrine, and migration capacity of P10 MSCs decreased significantly, accompanied by the increase of cellular senescence (P < 0.05). However, these functions, including PI3K/Akt activity of P10 MSCs, have been improved by c-Cbl downregulation (P < 0.05). Compared with P10 MSCs treatment, treatment with c-Cbl downregulated P10 MSCs accelerated diabetic wound healing, as defined by a more rapid wound closure (P < 0.05), more neovascularization (P < 0.05), and higher scores of wound histological assessment (P < 0.05) in a diabetic rat model. Our findings suggested that c-Cbl downregulation could attenuate the impairment of proangiogenic functions in MSCs induced by long-term culture in vitro and improve the effect of long-term cultured MSCs in promoting diabetic wound healing.
      Citation: Cell Transplantation
      PubDate: 2021-02-16T08:26:35Z
      DOI: 10.1177/0963689721989605
      Issue No: Vol. 30 (2021)
  • No Tumorigenicity of Allogeneic Induced Pluripotent Stem Cells in Major
           Histocompatibility Complex-matched Cynomolgus Macaques

    • Authors: Hirohito Ishigaki, Van Loi Pham, Jun Terai, Takako Sasamura, Cong Thanh Nguyen, Hideaki Ishida, Junko Okahara, Shin Kaneko, Takashi Shiina, Misako Nakayama, Yasushi Itoh, Kazumasa Ogasawara
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Tumorigenicity of induced pluripotent stem cells (iPSCs) is anticipated when cells derived from iPSCs are transplanted. It has been reported that iPSCs formed a teratoma in vivo in autologous transplantation in a nonhuman primate model without immunosuppression. However, there has been no study on tumorigenicity in major histocompatibility complex (MHC)-matched allogeneic iPSC transplantation with immune-competent hosts. To examine the tumorigenicity of allogeneic iPSCs, we generated four iPSC clones carrying a homozygous haplotype of the MHC. Two clones were derived from female fibroblasts by using a retrovirus and the other two clones were derived from male peripheral blood mononuclear cells by using Sendai virus (episomal approach). The iPSC clones were transplanted into allogenic MHC-matched immune-competent cynomolgus macaques. After transplantation of the iPSCs into subcutaneous tissue of an MHC-matched female macaque and into four testes of two MHC-matched male macaques, histological analysis showed no tumor, inflammation, or regenerative change in the excised tissues 3 months after transplantation, despite the results that iPSCs formed teratomas in immune-deficient mice and in autologous transplantation as previously reported. The results in the present study suggest that there is no tumorigenicity of iPSCs in MHC-matched allogeneic transplantation in clinical application.
      Citation: Cell Transplantation
      PubDate: 2021-02-16T08:26:33Z
      DOI: 10.1177/0963689721992066
      Issue No: Vol. 30 (2021)
  • Curcumin Supplementation Enhances Bone Marrow Mesenchymal Stem Cells to
           Promote the Anabolism of Articular Chondrocytes and Cartilage Repair

    • Authors: Rui Zhang, Qiaoxia Zhang, Zhiyu Zou, Zheng Li, Meng Jin, Jing An, Hui Li, Jianbing Ma
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Mesenchymal stem cells derived from bone marrows (BMSCs) and curcumin derived from turmeric were used for osteoarthritis (OA) treatment, respectively. We invested the effects of curcumin supplementation for BMSC therapeutic effects. In vitro, rat BMSCs were identified by dual-immunofluorescent staining of CD44 and CD90, and flow cytometry. Primary articular chondrocytes were identified by toluidine blue staining and immunofluorescent staining of Col2a1. EdU incorporation, migration assay, real-time quantitative polymerase chain reaction, and Western blot analyses were performed to evaluate the alterations of chondrocytes cocultured with BMSCs. In vivo, the rat model of OA was established by monoiodoacetic acid. After intra-articular injection of allogeneic BMSCs, articular cartilage damage and OA progression were evaluated by histological staining, and Osteoarthritis Research Society International and Mankin score evaluation. Although curcumin alone did not improve cell viability of primary articular chondrocytes, it promoted proliferation and migration of chondrocytes when cocultured with BMSCs. Meanwhile, the expression of anabolic genes in chondrocytes was remarkably increased both at mRNA and protein levels. In OA rats, curcumin and BMSCs cooperated to greatly promote articular cartilage repair and retard OA progression. Therefore, curcumin supplementation enhanced the BMSC function for the proliferation and migration of articular chondrocytes, and anabolic gene expression of extracellular matrix in articular chondrocytes in vitro, and the generation of articular cartilage in vivo. Our study shed light on the potential clinical application of curcumin cooperated with BMSCs in cartilage repair for OA treatment.
      Citation: Cell Transplantation
      PubDate: 2021-02-16T08:26:33Z
      DOI: 10.1177/0963689721993776
      Issue No: Vol. 30 (2021)
  • Thrombopoietin Promotes Cell Proliferation and Attenuates Apoptosis of
           Aplastic Anemia Serum-Treated 32D Cells via Activating STAT3/STAT5
           Signaling Pathway and Modulating Apoptosis-Related Mediators

    • Authors: Juan Qian, Xin Cao, Qian Shen, Yi-feng Cai, Wei Lu, Hong Yin, Xue-fen You, Hong Liu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The present study aimed to investigate the effect and possible mechanism of recombinant human thrombopoietin (rhTPO) on mouse 32D cells (a mouse myeloid progenitor cell line) treated with serum from patients with aplastic anemia and to elucidate the potential mechanism of rhTPO in the treatment of aplastic anemia. After treatment with aplastic anemia serum, the apoptotic rate of 32D cells was increased and the proliferation of 32D cells was significantly inhibited. rhTPO reduced the apoptotic rate and promoted the proliferation of 32D cells, while rhTPO failed to restore the cell proliferation of 32D cells from aplastic anemia serum group to the normal level as compared to that from the normal serum group. The phosphorylation level of STAT3 protein was higher, and the phosphorylation level of STAT5 protein was lower in 32D cells from aplastic anemia serum group than that in normal serum group. After rhTPO treatment, the phosphorylation level of STAT3 protein in aplastic anemia serum group was decreased and the phosphorylation level of STAT5 protein was increased. The expression levels of Survivin and Bcl-2 were significantly decreased in 32D cells from aplastic anemia serum group, which were significantly increased after rhTPO treatment. The expression level of Bax protein in 32D cells from the normal serum group after rhTPO treatment was significantly decreased; while the mRNA expression level of Bax was not affected by rhTPO. The expression levels of Bax mRNA and protein were significantly up-regulated in 32D cells from aplastic anemia serum group, which was significantly decreased by rhTPO treatment. In conclusion, our results indicated that aplastic anemia serum impaired proliferative potential and enhanced apoptosis of 32D cells. Further mechanistic studies revealed that rhTPO promoted cell proliferation and attenuated apoptosis of aplastic anemia serum-treated 32D cells via activating STAT3/STAT5 signaling pathway and modulating apoptosis-related mediators.
      Citation: Cell Transplantation
      PubDate: 2021-02-15T07:45:10Z
      DOI: 10.1177/0963689720980367
      Issue No: Vol. 30 (2021)
  • Isofraxidin Inhibits Receptor Activator of Nuclear Factor-κB
           Ligand–Induced Osteoclastogenesis in Bone Marrow–Derived Macrophages
           Isolated from Sprague–Dawley Rats by Regulating NF-κB/NFATc1 and
           Akt/NFATc1 Signaling Pathways

    • Authors: Wei Wang, Bo Wang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Osteoporosis is a common bone disease that is characterized by decreased bone mass and fragility fractures. Isofraxidin is a hydroxy coumarin with several biological and pharmacological activities including an anti-osteoarthritis effect. However, the role of isofraxidin in osteoporosis has not yet been investigated. In the present study, we used receptor activator of nuclear factor-κB ligand (RANKL) to induce osteoclast formation in primary bone marrow macrophages (BMMs). Our results showed that RANKL treatment significantly increased tartrate-resistant acid phosphatase (TRAP) activity, as well as the expression of osteoclastogenesis-related markers including MMP-9, c-Src, and cathepsin K at both mRNA and protein levels; however, these effects were inhibited by isofraxidin in BMMs. In addition, luciferase reporter assay demonstrated that isofraxidin treatment suppressed the RANKL-induced an increase in nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) transcriptional activity. Besides, the decreased expression level of IκBα and increased levels of p-p65, p-IκBα, and p-Akt in RANKL-induced BMMs were attenuated by isofraxidin. Moreover, NFATc1 overexpression rescued the anti-osteoclastogenic effect of isofraxidin with increased expression levels of MMP-9, c-Src, and cathepsin K. Taken together, these findings indicated that isofraxidin inhibited RANKL-induced osteoclast formation in BMMs via inhibiting the activation of NF-κB/NFATc1 and Akt/NFATc1 signaling pathways. Thus, isofraxidin might be a therapeutic agent for the treatment of osteoporosis.
      Citation: Cell Transplantation
      PubDate: 2021-02-12T08:57:25Z
      DOI: 10.1177/0963689721990321
      Issue No: Vol. 30 (2021)
  • LINC00461 Promoted Endometrial Carcinoma Growth and Migration by Targeting
           MicroRNA-219-5p/Cyclooxygenase-2 Signaling Axis

    • Authors: Yu Wang, Lili Yin
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Endometrial carcinoma (EC) ranks as the most common female genital cancer in developed countries. Lately, more and more long noncoding RNAs (lncRNAs) have been identified as vital regulators in numerous physiological and pathological processes, including EC. However, the expression pattern and precise functions of different lncRNAs in EC remain unclear. In this study, we reported LINC00461 was upregulated in EC patient tissues and cell lines. In addition, LINC00461 knockdown could remarkably suppress cell proliferation, cell cycle progression, cell migration, and promote cell apoptosis in EC cells. We discovered LINC00461 could sponge microRNA-219-5p (miR-219-5p) and suppress its expression, thereby upregulating expression level of miR-219-5p’s target, cyclooxygenase-2 (COX-2). In vivo animal models, LINC00461 knockdown inhibited tumor growth by increasing miR-219-5p level and reducing COX-2 expression, thus confirming LINC00461 functions as an oncogene in EC. In this study, a novel regulatory role of LINC00461/miR-219-5p/COX-2 axis was systematically investigated in context of EC, with the aim to provide promising intervention targets for EC therapy from bench to clinic.
      Citation: Cell Transplantation
      PubDate: 2021-02-12T08:57:24Z
      DOI: 10.1177/0963689721989616
      Issue No: Vol. 30 (2021)
  • Regeneration in Experimental Alveolar Bone Defect Using Human Umbilical
           Cord Mesenchymal Stem Cells

    • Authors: Akiko Toyota, Rei Shinagawa, Mikiko Mano, Kazuyuki Tokioka, Naoto Suda
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Cleft lip and palate is a congenital disorder including cleft lip, and/or cleft palate, and/or alveolar cleft, with high incidence.The alveolar cleft causes morphological and functional abnormalities. To obtain bone bridge formation and continuous structure between alveolar clefts, surgical interventions are performed from infancy to childhood. However, desirable bone bridge formation is not obtained in many cases. Regenerative medicine using mesenchymal stem cells (MSCs) is expected to be a useful strategy to obtain sufficient bone bridge formation between alveolar clefts. In this study, we examined the effect of human umbilical cord-derived MSCs by transplantation into a rat experimental alveolar cleft model. Human umbilical cords were digested enzymatically and the isolated cells were collected (UC-EZ cells). Next, CD146-positive cells were enriched from UC-EZ cells by magnetic-activated cell sorting (UC-MACS cells). UC-EZ and UC-MACS cells showed MSC gene/protein expression, in vitro. Both cells had multipotency and could differentiate to osteogenic, chondrogenic, and adipogenic lineages under the differentiation-inducing media. However, UC-EZ cells lacked Sox2 expression and showed the lower ratio of MSCs than UC-MACS cells. Thus, UC-MACS cells were transplanted with hydroxyapatite and collagen (HA + Col) into alveolar cleft model to evaluate bone formation in vivo. The results of micro computed tomography and histological staining showed that UC-MACS cells with HA + Col induced more abundant bone formation between the experimental alveolar clefts than HA + Col implantation only. Cells immunopositive for osteopontin were accumulated along the bone surface and some of them were embedded in the bone. Cells immunopositive for human-specific mitochondria were aligned along the newly formed bone surface and in the new bone, suggesting that UC-MACS cells contributed to the bone bridge formation between alveolar clefts. These findings indicate that human umbilical cords are reliable bioresource and UC-MACS cells are useful for the alveolar cleft regeneration.
      Citation: Cell Transplantation
      PubDate: 2021-02-12T08:56:58Z
      DOI: 10.1177/0963689720975391
      Issue No: Vol. 30 (2021)
  • CircRNA Circ-ITCH Inhibits the Proliferation and Invasion of Glioma Cells
           Through Targeting the miR-106a-5p/SASH1 Axis

    • Authors: Wei Chen, Ming Wu, Si-Tong Cui, Yue Zheng, Zhen Liu, Liang-Sheng Luo
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Circ-ITCH, a novel circRNA, was generated from several exons of itchy E3 ubiquitin protein ligase (ITCH). Recently, circ-ITCH has been demonstrated to be involved in cancer development. However, there have been few investigations on the specific role of circ-ITCH in glioma. In this study, we performed quantitative real-time polymerase chain reaction analysis and identified that circ-ITCH was significantly downregulated in glioma tissues and cell lines. The function assays showed that upregulation of circ-ITCH inhibited glioma cell proliferation and invasion in vitro as well as reduced cell growth in vivo. Moreover, miR-106a-5p was found serving as a target of circ-ITCH and miR-106a-5p mimics could reverse the inhibitory effect of circ-ITCH on glioma cell proliferation and invasion. We also revealed that circ-ITCH increased SASH1 expression by sponging miR-106a-5p in glioma cells. In addition, SASH1 downregulation could abrogate the suppressive effect of circ-ITCH on glioma progression. Taken together, our results suggested that circ-ITCH could suppress glioma cell proliferation and invasion via regulating the miR-106a-5p/SASH1 axis, elucidating a novel molecular target for glioma treatment.
      Citation: Cell Transplantation
      PubDate: 2021-02-11T05:45:18Z
      DOI: 10.1177/0963689720983785
      Issue No: Vol. 30 (2021)
  • Stem Cell Therapy for Spinal Cord Injury

    • Authors: Liyi Huang, Chenying Fu, Feng Xiong, Chengqi He, Quan Wei
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Traumatic spinal cord injury (SCI) results in direct and indirect damage to neural tissues, which results in motor and sensory dysfunction, dystonia, and pathological reflex that ultimately lead to paraplegia or tetraplegia. A loss of cells, axon regeneration failure, and time-sensitive pathophysiology make tissue repair difficult. Despite various medical developments, there are currently no effective regenerative treatments. Stem cell therapy is a promising treatment for SCI due to its multiple targets and reactivity benefits. The present review focuses on SCI stem cell therapy, including bone marrow mesenchymal stem cells, umbilical mesenchymal stem cells, adipose-derived mesenchymal stem cells, neural stem cells, neural progenitor cells, embryonic stem cells, induced pluripotent stem cells, and extracellular vesicles. Each cell type targets certain features of SCI pathology and shows therapeutic effects via cell replacement, nutritional support, scaffolds, and immunomodulation mechanisms. However, many preclinical studies and a growing number of clinical trials found that single-cell treatments had only limited benefits for SCI. SCI damage is multifaceted, and there is a growing consensus that a combined treatment is needed.
      Citation: Cell Transplantation
      PubDate: 2021-02-09T11:34:55Z
      DOI: 10.1177/0963689721989266
      Issue No: Vol. 30 (2021)
  • Are RNA-Based Tests Sufficient for COVID-19 Diagnosis' An Inspiration
           of Three Asymptomatic Cases

    • Authors: Tao Hu, Xiao Liu, Qinan Yin, Xingting Duan, Li Yan
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      In this work, we discovered a new phenomenon—asymptomatic COVID-19 infection, or covert case, during the pandemic. All the 3 patients had a history of exposure, with no symptoms, and no abnormalities were found in computed tomography scan or lab tests. Except for case 2, the other patients’ severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) nucleic acid tests were negative. But their anti-SARS-COV-2 nucleocapsid antibody showed a dynamic trend, consistent with the process of virus infection and clearance. A growing number of asymptomatic or covert cases need more attention. Lack of surveillance may lead to another outbreak. We hope to demonstrate our cases to attract the attention of governments or health authorities that covert cases should be the focus as well.
      Citation: Cell Transplantation
      PubDate: 2021-02-08T02:25:05Z
      DOI: 10.1177/0963689720985453
      Issue No: Vol. 30 (2021)
  • Three-dimensional Differentiated Human Mesenchymal Stem Cells Exhibit
           Robust Antifibrotic Potential and Ameliorates Mouse Liver Fibrosis

    • Authors: Ja Sung Choi, Young-Jin Park, Sung-Whan Kim
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Recently, three-dimensional (3D)-cultured adipose mesenchymal stem cells (ASCs) have provided an effective therapy for liver fibrosis. This study aimed to enhance the potential of human ASCs for antifibrosis or hepatocyte regeneration using a 3D culture system and investigate their therapeutic mechanism in experimental liver fibrosis. ASC-3Dc were generated in a 3D culture system and stimulated with four growth factors, namely epidermal growth factor, insulin-like growth factor (IGF)-1, fibroblast growth factor-2, and vascular endothelial growth factor-A. The expression levels of antifibrotic or hepatic regeneration factors were then measured using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The therapeutic effects of ASC-3Dc were determined using a liver fibrosis model induced by thioacetamide. Histological analysis was performed to elucidate the therapeutic mechanism. ASC-3Dc exhibited high levels of hepatocyte growth factor (HGF), IGF-1, stromal cell-derived factor (SDF)-1 genes, and protein expression. In addition, injecting ASC-3Dc significantly prevented hepatic fibrosis and improved liver function in vivo. Moreover, high numbers of ki-67-expressing hepatocytes were detected in the ASC-3Dc-injected livers. Albumin-expressing ASC-3Dc engrafted in fibrotic livers augmented HGF expression. Thus, short-term 3D-cultured ASCs may be a novel alternative to the conventional treatment for liver damage in clinical settings.
      Citation: Cell Transplantation
      PubDate: 2021-02-08T02:25:04Z
      DOI: 10.1177/0963689720987525
      Issue No: Vol. 30 (2021)
  • Successful Treatment of a 19-Month-Old Boy with Hepatitis Associated
           Aplastic Anemia by Infusion of Umbilical Cord-Derived Mesenchymal Stromal
           Cells: A Case Report

    • Authors: Liu Fang, Lim Meikuang, Guo Ye, Chen Xiaojuan, Yang Wenyu, Ruan Min, Chang Lixian, Wang Weiqiang, Han Zhibo, Han Zhongchao, Zhu Xiaofan
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Here we presented a case of a 19-month-old boy who developed severe aplastic anemia postacute hepatitis. He was treated successfully with the umbilical cord-derived mesenchymal stromal cells (UC-MSCs) infusion and cyclosporine A (CsA). The boy achieved both hematopoietic recovery and normal lymphocyte proportion. So far, his condition still remains stable. To our knowledge, there is a rare previous report on the utility of MSCs infusion for the treatment of hepatitis-associated aplastic anemia (HAAA). Considering the efficacy, safety, and strong operability, particularly for pediatric patient, the infusion of UC-MSCs combined with CsA could be an effective alternative for the treatment of HAAA.
      Citation: Cell Transplantation
      PubDate: 2021-02-02T10:00:22Z
      DOI: 10.1177/0963689720977144
      Issue No: Vol. 30 (2021)
  • Upregulation of ETV2 Expression Promotes Endothelial Differentiation of
           Human Dental Pulp Stem Cells

    • Authors: Jing Li, Youming Zhu, Na Li, Tao Wu, Xianyu Zheng, Boon chin Heng, Duohong Zou, Jianguang Xu
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      The lack of vasculogenesis often hampers the survivability and integration of newly engineered tissue grafts within the host. Autologous endothelial cells (ECs) are an ideal cell source for neovascularization, but they are limited by their scarcity, lack of proliferative capacity, and donor site morbidity upon isolation. The objective of this study was to determine whether differentiation of human dental pulp stem cells (DPSCs) into the endothelial lineage can be enhanced by recombinant ETV2 overexpression. DPSCs were extracted from fresh dental pulp tissues. ETV2 overexpression in DPSCs was achieved by lentiviral infection and cellular morphological changes were evaluated. The mRNA and protein expression levels of endothelial-specific markers were assessed through quantitative real-time polymerase chain reaction, western blot, immunofluorescence staining, and flow cytometry. The tube formation assay and Matrigel plug assay were also performed to evaluate the angiogenic potential of the ETV2-transduced cells in vitro and in vivo, respectively. Additionally, proteomic analysis was performed to analyze global changes in protein expression following ETV2 overexpression. After lentiviral infection, ETV2-overexpressing DPSCs showed endothelial-like morphology. Compared with control DPSCs, significantly higher mRNA and protein expression levels of endothelial-specific genes, including CD31, VE-Cadherin, VEGFR1, and VEGFR2, were detected in ETV2-overexpressing DPSCs. Moreover, ETV2 overexpression enhanced capillary-like tube formation on Matrigel in vitro, as well as neovascularization in vivo. In addition, comparative proteomic profiling showed that ETV2 overexpression upregulated the expression of vascular endothelial growth factor (VEGF) receptors, which was indicative of increased VEGF signaling. Taken together, our results indicate that ETV2 overexpression significantly enhanced the endothelial differentiation of DPSCs. Thus, this study shows that DPSCs can be a promising candidate cell source for tissue engineering applications.
      Citation: Cell Transplantation
      PubDate: 2021-02-01T06:26:10Z
      DOI: 10.1177/0963689720978739
      Issue No: Vol. 30 (2021)
  • Propofol Inhibits the Proliferation, Migration, and Stem-like Properties
           of Bladder Cancer Mainly by Suppressing the Hedgehog Pathway

    • Authors: Gang Li, Xu Zhang, Xiangyang Guo, Yi Li, Chong Li
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Bladder cancer is one of the most common malignancies. The existence of bladder cancer stem cells (BCSCs) has been suggested to underlie bladder tumor initiation and recurrence. Propofol is a commonly used intravenous anesthetic. Here, we find that propofol can dramatically block the activation of Hedgehog pathway in BCSCs. The propofol strongly repressed the growth of cancer cells. Attenuated proliferation and enhanced apoptosis of tumor cells were observed upon propofol stimulation. Furthermore, propofol reduced the self-renewal ability of BCSCs as well as the tumor formation. In conclusion, propofol is potentially used as a novel therapeutic agent for bladder cancer by targeting self-renewal through inhibiting Hedgehog pathway.
      Citation: Cell Transplantation
      PubDate: 2021-02-01T06:26:09Z
      DOI: 10.1177/0963689720985113
      Issue No: Vol. 30 (2021)
  • Human Embryonic Stem Cell–derived Neural Crest Cells Promote Sprouting
           and Motor Recovery Following Spinal Cord Injury in Adult Rats

    • Authors: Iwan Jones, Liudmila N. Novikova, Mikael Wiberg, Leif Carlsson, Lev N. Novikov
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Spinal cord injury results in irreversible tissue damage and permanent sensorimotor impairment. The development of novel therapeutic strategies that improve the life quality of affected individuals is therefore of paramount importance. Cell transplantation is a promising approach for spinal cord injury treatment and the present study assesses the efficacy of human embryonic stem cell–derived neural crest cells as preclinical cell-based therapy candidates. The differentiated neural crest cells exhibited characteristic molecular signatures and produced a range of biologically active trophic factors that stimulated in vitro neurite outgrowth of rat primary dorsal root ganglia neurons. Transplantation of the neural crest cells into both acute and chronic rat cervical spinal cord injury models promoted remodeling of descending raphespinal projections and contributed to the partial recovery of forelimb motor function. The results achieved in this proof-of-concept study demonstrates that human embryonic stem cell–derived neural crest cells warrant further investigation as cell-based therapy candidates for the treatment of spinal cord injury.
      Citation: Cell Transplantation
      PubDate: 2021-02-01T06:26:08Z
      DOI: 10.1177/0963689720988245
      Issue No: Vol. 30 (2021)
  • Estrogen and Androgen Receptor Inhibitors: Unexpected Allies in the Fight
           Against COVID-19

    • Authors: Sara Bravaccini, Eugenio Fonzi, Michela Tebaldi, Davide Angeli, Giovanni Martinelli, Fabio Nicolini, Paola Parrella, Massimiliano Mazza
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Translational RelevanceNo prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.
      Citation: Cell Transplantation
      PubDate: 2021-02-01T06:26:05Z
      DOI: 10.1177/0963689721991477
      Issue No: Vol. 30 (2021)
  • Shikonin Inhibits Cholangiocarcinoma Cell Line QBC939 by Regulating
           Apoptosis, Proliferation, and Invasion

    • Authors: Chang Liu, Li-Qian Xuan, Kai Li, Zhuo Feng, Chan Lv, Xing-Jia Li, Xiao-Dan Ji, Rong Wan, Jie Shen
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      This study was designed to clarify whether Shikonin causes proliferation, apoptosis, and invasion in cholangiocarcinoma cells and to investigate the mechanism of action. QBC939 cells were cultured with different doses of Shikonin, and then 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium assay was used to detect cell viability. Apoptosis of cells was detected using flow cytometry with Annexin V/propidium iodide (PI) assay after being stained with Hoechst 33242. The role of Shikonin on the invasive and metastasis ability was detected using Transwell invasion assay. Real-time polymerase chain reaction and Western blotting were used to detect the expression of caspase-3, caspase-8, epidermal growth factor receptor (EGFR), and matrix metalloproteinase (MMP)-9. Shikonin inhibited proliferation and invasive ability of QBC939 cells in a dose-dependent manner; at the same time, apoptosis of cells was also observed in a concentration-dependent fashion. Moreover, Annexin V/PI assay and Transwell invasion assay results indicated that Shikonin induced apoptosis and invasion inhibitory probably due to upregulation of caspase-3 and caspase-8 expression and downregulation of MMP-9 and EGFR expression in a concentration-dependent fashion. Shikonin could enhance apoptosis and inhibit proliferation and invasion of QBC939 cells; such biological behaviors mainly occurred via upregulating the expression of caspase-3 and caspase-8 and downregulating the expression of MMP-9 and EGFR.
      Citation: Cell Transplantation
      PubDate: 2021-01-29T07:24:44Z
      DOI: 10.1177/0963689720979162
      Issue No: Vol. 30 (2021)
  • LncRNA PCAT1 Interacts with DKC1 to Regulate Proliferation, Invasion and
           Apoptosis in NSCLC Cells via the VEGF/AKT/Bcl2/Caspase9 Pathway

    • Authors: Shi-Yuan Liu, Zhi-Yu Zhao, Zhe Qiao, Shao-Min Li, Wei-Ning Zhang
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Long noncoding RNAs (lncRNAs) are increasingly recognized as indispensable components of the regulatory network in the progression of various cancers, including nonsmall cell lung cancer (NSCLC). The lncRNA prostate cancer associated transcript 1 (PCAT1) has been involved in tumorigenesis of multiple malignant solid tumors, but it is largely unknown that what is the role of lncRNA-PCAT1 and how it functions in the progression of lung cancer. Herein, we observed that lncRNA PCAT1 expression was upregulated in both human NSCLC tissues and cell lines, which was determined by qualitative polymerase chain reaction analysis. Then, gain-and loss-of-function manipulations were performed in A549 cells by transfection with a specific short interfering RNA against PCAT1 or a pcDNA-PCAT1 expression vector. The results showed that PCAT1 not only promoted NSCLC cell proliferation and invasion but also inhibited cell apoptosis. Bioinformatics and expression correlation analyses revealed that there was a potential interaction between PCAT1 and the dyskerin pseudouridine synthase 1 (DKC1) protein, an RNA-binding protein. Then, RNA pull-down assays with biotinylated probes and transcripts both confirmed that PCAT1 directly bounds with DKC1 that could also promote NSCLC cell proliferation and invasion and inhibit cell apoptosis. Moreover, the effects of PCAT1 and DKC1 on NSCLC functions are synergistic. Furthermore, PCAT1 and DKC1 activated the vascular endothelial growth factor (VEGF)/protein kinase B (AKT)/Bcl-2/caspase9 pathway in NSCLC cells, and inhibition of epidermal growth factor receptor, AKT, or Bcl-2 could eliminate the effect of PCAT1/DKC1 co-overexpression on NSCLC cell behaviors. In conclusion, lncRNA PCAT1 interacts with DKC1 to regulate proliferation, invasion, and apoptosis in NSCLC cells via the VEGF/AKT/Bcl-2/caspase9 pathway.
      Citation: Cell Transplantation
      PubDate: 2021-01-19T09:38:32Z
      DOI: 10.1177/0963689720986071
      Issue No: Vol. 30 (2021)
  • Human Keratinocytes Adopt Neuronal Fates After In Utero Transplantation in
           the Developing Rat Brain

    • Authors: Andrea Tenorio-Mina, Daniel Cortés, Joel Esquivel-Estudillo, Adolfo López-Ornelas, Alejandro Cabrera-Wrooman, Rolando Lara-Rodarte, Itzel Escobedo-Avila, Fernanda Vargas-Romero, Diana Toledo-Hernández, Enrique Estudillo, Juan José Acevedo-Fernández, Jesús Santa-Olalla Tapia, Iván Velasco
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Human skin contains keratinocytes in the epidermis. Such cells share their ectodermal origin with the central nervous system (CNS). Recent studies have demonstrated that terminally differentiated somatic cells can adopt a pluripotent state, or can directly convert its phenotype to neurons, after ectopic expression of transcription factors. In this article we tested the hypothesis that human keratinocytes can adopt neural fates after culturing them in suspension with a neural medium. Initially, keratinocytes expressed Keratins and Vimentin. After neural induction, transcriptional upregulation of NESTIN, SOX2, VIMENTIN, SOX1, and MUSASHI1 was observed, concomitant with significant increases in NESTIN detected by immunostaining. However, in vitro differentiation did not yield the expression of neuronal or astrocytic markers. We tested the differentiation potential of control and neural-induced keratinocytes by grafting them in the developing CNS of rats, through ultrasound-guided injection. For this purpose, keratinocytes were transduced with lentivirus that contained the coding sequence of green fluorescent protein. Cell sorting was employed to select cells with high fluorescence. Unexpectedly, 4 days after grafting these cells in the ventricles, both control and neural-induced cells expressed green fluorescent protein together with the neuronal proteins βIII-Tubulin and Microtubule-Associated Protein 2. These results support the notion that in vivo environment provides appropriate signals to evaluate the neuronal differentiation potential of keratinocytes or other non-neural cell populations.
      Citation: Cell Transplantation
      PubDate: 2021-01-13T07:34:04Z
      DOI: 10.1177/0963689720978219
      Issue No: Vol. 30 (2021)
  • hsa_circ_0023409 Accelerates Gastric Cancer Cell Growth and Metastasis
           Through Regulating the IRS4/PI3K/AKT Pathway

    • Authors: Jian Li, Yongjing Yang, Dequan Xu, Ling Cao
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Gastric cancer (GC) is a big threat to human life and health. Circular RNAs (circRNAs), a subclass of noncoding RNAs, were reported to play a critical role in GC progression. Here, we investigated the role of a novel circRNA named hsa_circ_0023409 in GC and its mechanism. Hsa_circ_0023409 expression in GC and adjacent tissues was examined by quantitative real-time polymerase chain reaction and in situ hybridization. The functions of hsa_circ_0023409 in GC cells were assessed both in vitro and in vivo. Immunofluorescence staining was performed for the localization of hsa_circ_0023409 and miR-542-3p in cells. The interaction between hsa_circ_0023409 and miR-542-3p, and miR-542-3p and insulin receptor substrate 4 (IRS4) was detected by dual-luciferase reporter assay. The effect of hsa_circ_0023409, miR-542-3p, and IRS4 on IRS4/phosphatidylinositol 3-kinase (PI3K)/AKT pathway was detected by western blot. The results showed that hsa_circ_0023409 was mainly located in cytoplasm and highly expressed in GC tissues and cells. Moreover, hsa_circ_0023409 showed positive correlation with tumor size, histological grade, and tumor–node–metastasis staging of GC patients. Functional studies showed that hsa_circ_0023409 promoted cell viability, proliferation, migration, and invasion and suppressed apoptosis in GC. Mechanism studies demonstrated that hsa_circ_0023409 upregulated IRS4 via sponging miR-542-3p in GC cells. Furthermore, IRS4 overexpression activated the PI3K/AKT pathway and reversed the inhibitory effect of hsa_circ_0023409 knockdown on the PI3K/AKT pathway. Taken together, we prove that hsa_circ_0023409 activates IRS4/PI3K/AKT pathway by acting as a sponge for miR-542-3p, thus promoting GC progression, indicating that hsa_circ_0023409 may serve as a potential target for treatment of GC and prognosis of GC patients.
      Citation: Cell Transplantation
      PubDate: 2021-01-13T06:38:40Z
      DOI: 10.1177/0963689720975390
      Issue No: Vol. 30 (2021)
  • LncRNA CCDC26 Interacts with CELF2 Protein to Enhance Myeloid Leukemia
           Cell Proliferation and Invasion via the circRNA_ANKIB1/miR-195-5p/PRR11

    • Authors: Chengliang Li, Jianjun Mu, Yingpeng Shi, Hong Xin
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      LncRNA CCDC26 is aberrantly expressed in myeloid leukemia (ML) and promotes myeloid leukemia progression, but the potential mechanism of CCDC26 in regulating ML progression is unclear. In this study, we observed that lncRNA CCDC26 was upregulated in both chronic and acute ML cell lines. LncRNA CCDC26 promoted the proliferation and invasion of K562 and HL-60 cells, which was determined by cell counting kit-8 test and Transwell invasion assay. Flow cytometry showed that lncRNA CCDC26 inhibited cell apoptosis. Bioinformatics and expression correlation analyses revealed that there was a potential interaction between CCDC26 and CUGBP Elav-like family member 2 (CELF2) protein, an RNA bind protein (RBP). Then the relationship between CCDC26 and the RBP CELF2 was identified by using RNA pull-down and RNA immunoprecipitation (RNA-IP) assays. Further analysis showed that overexpression of CCDC26 could noticeably upregulate circRNA_ANKIB1 expression via sponging CELF2. Subsequently, we found that overexpressed circRNA_ANKIB1 could significantly promote proline rich 11 (PRR11) protein expression by sponging miR-195a-5p. Moreover, PRR11 was also upregulated by CCDC26 and downregulated by CELF2. Mechanically, we uncovered that the miR-195a-5p inhibitor activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways through upregulating PRR11 protein expression. Furthermore, the inhibitors of AKT, p65-NF-κB, or Bcl-2 could inhibit the effect of the miR-195a-5p inhibitor on ML cell behaviors. In conclusion, lncRNA CCDC26 could upregulate PRR11 protein expression by sponging miR-195a-5p, thereby activating the PI3K/AKT and NF-κB pathways to enhance ML cell proliferation and invasion and suppress cell apoptosis.
      Citation: Cell Transplantation
      PubDate: 2021-01-13T06:33:19Z
      DOI: 10.1177/0963689720986080
      Issue No: Vol. 30 (2021)
  • Delayed Treatment with Human Dental Pulp Stem Cells Accelerates Functional
           Recovery and Modifies Responses of Peri-Infarct Astrocytes Following
           Photothrombotic Stroke in Rats

    • Authors: Wai Ping Yew, Natalia D. Djukic, Jaya S. P. Jayaseelan, Xenia Kaidonis, Karlea L. Kremer, Fong Chan Choy, Richard J. Woodman, Simon A. Koblar, Neil R. Sims
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Dental pulp contains multipotent mesenchymal stem cells that improve outcomes when administered early after temporary middle cerebral artery occlusion in rats. To further assess the therapeutic potential of these cells, we tested whether functional recovery following stroke induced by photothrombosis could be modified by a delayed treatment that was initiated after the infarct attained maximal volume. Photothrombosis induces permanent focal ischemia resulting in tissue changes that better reflect key aspects of the many human strokes in which early restoration of blood flow does not occur. Human dental pulp stem cells (approximately 400 × 103 viable cells) or vehicle were injected into the infarct and adjacent brain tissue of Sprague-Dawley rats at 3 days after the induction of unilateral photothrombotic stroke in the sensorimotor cortex. Forepaw function was tested up to 28 days after stroke. Cellular changes in peri-infarct tissue at 28 days were assessed using immunohistochemistry. Rats treated with the stem cells showed faster recovery compared with vehicle-treated animals in a test of forelimb placing in response to vibrissae stimulation and in first attempt success in a skilled forelimb reaching test. Total success in the skilled reaching test and forepaw use during exploration in a Perspex cylinder were not significantly different between the 2 groups. At 28 days after stroke, rats treated with the stem cells showed decreased immunolabeling for glial fibrillary acidic protein in tissue up to 1 mm from the infarct, suggesting decreased reactive astrogliosis. Synaptophysin, a marker of synapses, and collagen IV, a marker of capillaries, were not significantly altered at this time by the stem-cell treatment. These results indicate that dental pulp stem cells can accelerate recovery without modifying initial infarct formation. Decreases in reactive astrogliosis in peri-infarct tissue could have contributed to the change by promoting adaptive responses in neighboring neurons.
      Citation: Cell Transplantation
      PubDate: 2021-01-12T10:17:32Z
      DOI: 10.1177/0963689720984437
      Issue No: Vol. 30 (2021)
  • Application of Plastic Sheet Barrier and Video Intubating Stylet to
           Protect Tracheal Intubators During Coronavirus Disease 2019 Pandemic: A
           Taiwan Experience

    • Authors: Hsiang-Ning Luk, Yao-Lin Yang, Ching-Hsuan Huang, I-Min Su, Phil B. Tsai
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Since its outbreak in China, the Coronavirus disease 2019 (COVID-19) pandemic has caused worldwide disaster. Globally, there have been 71,581,532 confirmed cases of COVID-19, including 1,618,374 deaths, reported to World Health Organization (data retrieved on December 16, 2020). Currently, no treatment modalities for COVID-19 (e.g., vaccines or antiviral drugs) with confirmed efficacy and safety are available. Although the possibilities and relevant challenges of some alternatives (e.g., use of stem cells as immunomodulators) have been proposed, the personal protective equipment is still the only way to protect and lower infection rates of COVID-19 among healthcare workers and airway managers (intubators). In this article, we described the combined use of a plastic sheet as a barrier with the intubating stylet for tracheal intubation in patients needing mechanical ventilation. Although conventional or video-assisted laryngoscopy is more popular and familiar to other groups around the world, we believe that the video-assisted intubating stylet technique is much easier to learn and master. Advantages of the video stylet include the creation of greater working distance between intubator and patient, less airway stimulation, and less pharyngeal space needed for endotracheal tube advancement. All the above features make this technique reliable and superior to other devices, especially when a difficult airway is encountered in COVID scenario. Meanwhile, we proposed the use of a flexible and transparent plastic sheet to serve as a barrier against aerosol and droplet spread during airway management. We demonstrated that the use of a plastic sheet would not interfere or hinder the intubator’s maneuvers during endotracheal intubation. Moreover, we demonstrated that the plastic sheet was effective in preventing the spread of mist and water spray in simulation models with a mannequin. In our experience, we found that this technique most effectively protected the intubator and other operating room personnel from infection during the COVID-19 pandemic.
      Citation: Cell Transplantation
      PubDate: 2021-01-11T06:21:37Z
      DOI: 10.1177/0963689720987527
      Issue No: Vol. 30 (2021)
  • Low-Intensity Pulsed Ultrasound Promotes Autophagy-Mediated Migration of
           Mesenchymal Stem Cells and Cartilage Repair

    • Authors: Peng Xia, Xinwei Wang, Qi Wang, Xiaoju Wang, Qiang Lin, Kai Cheng, Xueping Li
      Abstract: Cell Transplantation, Volume 30, Issue , January-December 2021.
      Mesenchymal stem cell (MSC) migration is promoted by low-intensity pulsed ultrasound (LIPUS), but its mechanism is unclear. Since autophagy is known to regulate cell migration, our study aimed to investigate if LIPUS promotes the migration of MSCs via autophagy regulation. We also aimed to investigate the effects of intra-articular injection of MSCs following LIPUS stimulation on osteoarthritis (OA) cartilage. For the in vitro study, rat bone marrow-derived MSCs were treated with an autophagy inhibitor or agonist, and then they were stimulated by LIPUS. Migration of MSCs was detected by transwell migration assays, and stromal cell-derived factor-1 (SDF-1) and C-X-C chemokine receptor type 4 (CXCR4) protein levels were quantified. For the in vivo study, a rat knee OA model was generated and treated with LIPUS after an intra-articular injection of MSCs with autophagy inhibitor added. The cartilage repair was assessed by histopathological analysis and extracellular matrix protein expression. The in vitro results suggest that LIPUS increased the expression of SDF-1 and CXCR4, and it promoted MSC migration. These effects were inhibited and enhanced by autophagy inhibitor and agonist, respectively. The in vivo results demonstrate that LIPUS significantly enhanced the cartilage repair effects of MSCs on OA, but these effects were blocked by autophagy inhibitor. Our results suggest that the migration of MSCs was enhanced by LIPUS through the activation autophagy, and LIPUS improved the protective effect of MSCs on OA cartilage via autophagy regulation.
      Citation: Cell Transplantation
      PubDate: 2021-01-08T08:59:02Z
      DOI: 10.1177/0963689720986142
      Issue No: Vol. 30 (2021)
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