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  Journal of Developmental Biology
  [4 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2221-3759
   Published by MDPI Homepage  [130 journals]
  • JDB, Vol. 3, Pages 25-56: Retinoic Acid and the Development of the

    • Authors: Gregory Kelly, Thomas Drysdale
      Pages: 25 - 56
      Abstract: Retinoic acid (RA) is an important signaling molecule in the development of the endoderm and an important molecule in protocols used to generate endodermal cell types from stem cells. In this review, we describe the RA signaling pathway and its role in the patterning and specification of the extra embryonic endoderm and different endodermal organs. The formation of endoderm is an ancient evolutionary feature and RA signaling appears to have coevolved with the vertebrate lineage. Towards that end, we describe how RA participates in many regulatory networks required for the formation of extraembryonic structures as well as the organs of the embryo proper.
      PubDate: 2015-04-20
      DOI: 10.3390/jdb3020025
      Issue No: Vol. 3, No. 2 (2015)
  • JDB, Vol. 3, Pages 57-70: Roles of Antioxidative Enzymes in Wound Healing

    • Authors: Toshihiro Kurahashi, Junichi Fujii
      Pages: 57 - 70
      Abstract: Since skin is the first barrier separating the body from the external environment, impaired wound healing can be life threatening to living organisms. Delayed healing processes are observed in animals under certain circumstances, such as advanced age, diabetes, and immunosuppression, but the underlying mechanisms of the abnormality remain elusive. Redox homeostasis is defined as the balance between the levels of reactive oxygen species (ROS) and antioxidants in which antioxidative enzymes play central roles in scavenging ROS. In addition to deleterious effects, ROS also exert beneficial functions on some cellular processes such as transducing phosphorylation signaling, but excessive antioxidants may impede the healing process. Hence, strict control over the amounts of antioxidants is desirable when applied for therapeutic purposes. Here we overview recent findings regarding the relationships between antioxidative enzymes and wound healing. Unveiling the role of antioxidative enzymes is expected to contribute to our understanding of the wound healing processes.
      PubDate: 2015-04-27
      DOI: 10.3390/jdb3020057
      Issue No: Vol. 3, No. 2 (2015)
  • JDB, Vol. 3, Pages 1: Acknowledgement to Reviewers of the Journal of
           Developmental Biology in 2014

    • Authors: JDB Office
      Pages: 1 - 1
      Abstract: The editors of the Journal of Developmental Biology would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2014:[...]
      PubDate: 2015-01-09
      DOI: 10.3390/jdb3010001
      Issue No: Vol. 3, No. 1 (2015)
  • JDB, Vol. 3, Pages 2-10: Strain-Dependent Gene Expression during Mouse
           Embryonic Palate Development

    • Authors: Jiu-Zhen Jin, Jixiang Ding
      Pages: 2 - 10
      Abstract: The effect of strain background on gene function in growth and development has been well documented. However, it has not been extensively reported whether the strain background affects the gene expression pattern. Here, we found that the expression of homeobox gene Meox-2 and FGF receptor 1 gene Fgfr1 during mouse palate development is strain-dependent. On the C57B6 inbred background, Meox-2 is expressed in the palatal outgrowth on Embryonic Day 11.5 (E11.5); the expression shifts posteriorly and is restricted to the back of palate on E14.5. On the Swiss Webster outbred background, Meox-2 expression covers both anterior and posterior regions with the same intensity from E12.5 to E14.5. On the Black Swiss background, Meox-2 expression also covers the entire palate A-P axis, but is much weaker in the anterior region on E14.5. Fgfr1 also displays distinct expression patterns in the palatal outgrowth on E11.5 in these three strains. On the Black Swiss outbred background, the expression is restricted to the anterior palatal outgrowth. In marked contrast, the expression in the Swiss Webster outbred strain is located exclusively in the posterior palate outgrowth on E11.5, whereas in the C57B6 inbred strain, the expression is undetectable in the palatal outgrowth on E11.5.
      PubDate: 2015-02-06
      DOI: 10.3390/jdb3010002
      Issue No: Vol. 3, No. 1 (2015)
  • JDB, Vol. 3, Pages 11-24: Inhibition of SERPINE1 Function Attenuates Wound
           Closure in Response to Tissue Injury: A Role for PAI-1 in
           Re-Epithelialization and Granulation Tissue Formation

    • Authors: Tessa Simone, Paul Higgins
      Pages: 11 - 24
      Abstract: Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is a prominent member of the serine protease inhibitor superfamily (SERPIN) and a causative factor of multi-organ fibrosis as well as a key regulator of the tissue repair program. PAI-1 attenuates pericellular proteolysis by inhibiting the catalytic activity of both urokinase and tissue-type protease activators (uPA and tPA) effectively modulating, thereby, plasmin-mediated fibrinolysis and the overall pericellular proteolytic cascade. PAI-1 also impacts cellular responses to tissue injury and stress situations (growth, survival, migration) by titering the locale and temporal activation of multimeric cell-surface signaling complexes. This review will describe PAI-1 structure and function and detail the role of PAI-1 in the tissue repair program with an emphasis on cutaneous wound healing.
      PubDate: 2015-03-02
      DOI: 10.3390/jdb3010011
      Issue No: Vol. 3, No. 1 (2015)
  • JDB, Vol. 2, Pages 198-209: A Novel Three-Dimensional Wound Healing Model

    • Authors: Zhuo Chen, Jessica Yang, Benjamin Wu, Bill Tawil
      Pages: 198 - 209
      Abstract: Wound healing is a well-orchestrated process, with various cells and growth factors coming into the wound bed at a specific time to influence the healing. Understanding the wound healing process is essential to generating wound healing products that help with hard-to-heal acute wounds and chronic wounds. The 2D scratch assay whereby a wound is created by scratching a confluent layer of cells on a 2D substrate is well established and used extensively but it has a major limitation—it lacks the complexity of the 3D wound healing environment. Established 3D wound healing models also have many limitations. In this paper, we present a novel 3D wound healing model that closely mimics the skin wound environment to study the cell migration of fibroblasts and keratinocytes. Three major components that exist in the wound environment are introduced in this new model: collagen, fibrin, and human foreskin fibroblasts. The novel 3D model consists of a defect, representing the actual wound, created by using a biopsy punch in a 3D collagen construct. The defect is then filled with collagen or with various solutions of fibrinogen and thrombin that polymerize into a 3D fibrin clot. Fibroblasts are then added on top of the collagen and their migration into the fibrin—or collagen—filled defect is followed for nine days. Our data clearly shows that fibroblasts migrate on both collagen and fibrin defects, though slightly faster on collagen defects than on fibrin defects. This paper shows the visibility of the model by introducing a defect filled with fibrin in a 3D collagen construct, thus mimicking a wound. Ongoing work examines keratinocyte migration on the defects of a 3D construct, which consists of collagen-containing fibroblasts. The model is also used to determine the effects of various growth factors, delivered in the wound defects, on fibroblasts’ and keratinocytes’ migration into the defects. Thus this novel 3D wound healing model provides a more complex wound healing assay than existing wound models.
      PubDate: 2014-12-19
      DOI: 10.3390/jdb2040198
      Issue No: Vol. 2, No. 4 (2014)
  • JDB, Vol. 2, Pages 210-229: Observations on Lumbar Spinal Cord Recovery
           after Lesion in Lizards Indicates Regeneration of a Cellular and Fibrous
           Bridge Reconnecting the Injured Cord

    • Authors: Lorenzo Alibardi
      Pages: 210 - 229
      Abstract: The lumbar spinal cords of lizards were transected, but after the initial paralysis most lizards recovered un-coordinated movements of hind limbs. At 25-45 days post-lesion about 50% of lizards were capable of walking with a limited coordination. Histological analysis showed that the spinal cord was transected and the ependyma of the central canal formed two enlargements to seal the proximal and distal ends of the severed spinal cord. Glial and few small neurons were formed while bridge axons crossed the gap between the proximal and the distal stumps of the transected spinal cord as was confirmed by retrograde tract-tracing technique. The bridging fibers likely derived from interneurons located in the central and dorsal grey matter of the proximal spinal cord stump suggesting they belong to the local central locomotory pattern generator circuit. The limited recovery of hind limb movements may derive from the regeneration or sprouting of short proprio-spinal axons joining the two stumps of the transected spinal cord. The present observations indicate that the study on spinal cord regeneration in lizards can give insights on the permissive conditions that favor nerve regeneration in amniotes.
      PubDate: 2014-12-19
      DOI: 10.3390/jdb2040210
      Issue No: Vol. 2, No. 4 (2014)
  • JDB, Vol. 2, Pages 158-173: Retinoic Acid-Induced Epidermal
           Transdifferentiation in Skin

    • Authors: Yoshihiro Akimoto, Mary Miyaji, Riyo Morimoto-Kamata, Yasuhiro Kosaka, Akiko Obinata
      Pages: 158 - 173
      Abstract: Retinoids function as important regulatory signaling molecules during development, acting in cellular growth and differentiation both during embryogenesis and in the adult animal. In 1953, Fell and Mellanby first found that excess vitamin A can induce transdifferentiation of chick embryonic epidermis to a mucous epithelium (Fell, H.B.; Mellanby, E. Metaplasia produced in cultures of chick ectoderm by high vitamin A. J. Physiol. 1953, 119, 470–488). However, the molecular mechanism of this transdifferentiation process was unknown for a long time. Recent studies demonstrated that Gbx1, a divergent homeobox gene, is one of the target genes of all-trans retinoic acid (ATRA) for this transdifferentiation. Furthermore, it was found that ATRA can induce the epidermal transdifferentiation into a mucosal epithelium in mammalian embryonic skin, as well as in chick embryonic skin. In the mammalian embryonic skin, the co-expression of Tgm2 and Gbx1 in the epidermis and an increase in TGF-β2 expression elicited by ATRA in the dermis are required for the mucosal transdifferentiation, which occurs through epithelial-mesenchymal interaction. Not only does retinoic acid (RA) play an important role in mucosal transdifferentiation, periderm desquamation, and barrier formation in the developing mammalian skin, but it is also involved in hair follicle downgrowth and bending by its effect on the Wnt/β-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families.
      PubDate: 2014-06-26
      DOI: 10.3390/jdb2030158
      Issue No: Vol. 2, No. 3 (2014)
  • JDB, Vol. 2, Pages 174-197: Retinoic Acid Signaling during Early Spinal
           Cord Development

    • Authors: Ruth del Corral, Aixa Morales
      Pages: 174 - 197
      Abstract: Retinoic acid signaling is required at several steps during the development of the spinal cord, from the specification of generic properties to the final acquisition of neuronal subtype identities, including its role in trunk neural crest development. These functions are associated with the production of retinoic acid in specific tissues and are highly dependent on context. Here, we review the defects associated with retinoic acid signaling manipulations, mostly in chick and mouse models, trying to separate the different processes where retinoic acid signaling is involved and to highlight common features, such as its ability to promote transitions along the neuronal differentiation cascade.
      PubDate: 2014-06-26
      DOI: 10.3390/jdb2030174
      Issue No: Vol. 2, No. 3 (2014)
  • JDB, Vol. 2, Pages 72-83: Retinoic Acid, under Cerebrospinal Fluid
           Control, Induces Neurogenesis during Early Brain Development

    • Authors: M. Alonso, Estela Carnicero, Raquel Carretero, Aníbal De la Mano, Jose Moro, Francisco Lamus, Cristina Martín, Angel Gato
      Pages: 72 - 83
      Abstract: One of the more intriguing subjects in neuroscience is how a precursor or stem cell is induced to differentiate into a neuron. Neurogenesis begins early in brain development and suddenly becomes a very intense process, which is related with the influence of Retinoic Acid. Here, using a biological test (F9-1.8 cells) in chick embryos, we show that “in vivo” embryonic cerebrospinal fluid regulates mesencephalic-rombencephalic Isthmic Retinoic Acid synthesis and this effect has a direct influence on mesencephalic neuroepithelial precursors, inducing a significant increase in neurogenesis. This effect is mediated by the Retinol Binding Protein present in the embryonic cerebrospinal fluid. The knowledge of embryonic neurogenetic stimulus could be useful in the control of adult brain neurogenesis.
      PubDate: 2014-04-08
      DOI: 10.3390/jdb2020072
      Issue No: Vol. 2, No. 2 (2014)
  • JDB, Vol. 2, Pages 84-100: Epicardium-Derived Heart Repair

    • Authors: Anke Smits, Paul Riley
      Pages: 84 - 100
      Abstract: In the last decade, cell replacement therapy has emerged as a potential approach to treat patients suffering from myocardial infarction (MI). The transplantation or local stimulation of progenitor cells with the ability to form new cardiac tissue provides a novel strategy to overcome the massive loss of myocardium after MI. In this regard the epicardium, the outer layer of the heart, is a tractable local progenitor cell population for therapeutic pursuit. The epicardium has a crucial role in formation of the embryonic heart. After activation and migration into the developing myocardium, epicardial cells differentiate into several cardiac cells types. Additionally, the epicardium provides instructive signals for the growth of the myocardium and coronary angiogenesis. In the adult heart, the epicardium is quiescent, but recent evidence suggests that it becomes reactivated upon damage and recapitulates at least part of its embryonic functions. In this review we provide an update on the current knowledge regarding the contribution of epicardial cells to the adult mammalian heart during the injury response.
      PubDate: 2014-04-10
      DOI: 10.3390/jdb2020084
      Issue No: Vol. 2, No. 2 (2014)
  • JDB, Vol. 2, Pages 101-116: The Epicardium in the Embryonic and Adult

    • Authors: Marina Peralta, Juan González-Rosa, Inês Marques, Nadia Mercader
      Pages: 101 - 116
      Abstract: The epicardium is the mesothelial outer layer of the vertebrate heart. It plays an important role during cardiac development by, among other functions, nourishing the underlying myocardium, contributing to cardiac fibroblasts and giving rise to the coronary vasculature. The epicardium also exerts key functions during injury responses in the adult and contributes to cardiac repair. In this article, we review current knowledge on the cellular and molecular mechanisms underlying epicardium formation in the zebrafish, a teleost fish, which is rapidly gaining status as an animal model in cardiovascular research, and compare it with the mechanisms described in other vertebrate models. We moreover describe the expression patterns of a subset of available zebrafish Wilms’ tumor 1 transgenic reporter lines and discuss their specificity, applicability and limitations in the study of epicardium formation.
      PubDate: 2014-04-11
      DOI: 10.3390/jdb2020101
      Issue No: Vol. 2, No. 2 (2014)
  • JDB, Vol. 2, Pages 117-137: Epicardial Origin of Resident Mesenchymal Stem
           Cells in the Adult Mammalian Heart

    • Authors: Naisana Asli, Munira Xaymardan, Richard Harvey
      Pages: 117 - 137
      Abstract: The discovery of stem and progenitor cells in the adult mammalian heart has added a vital dimension to the field of cardiac regeneration. Cardiac-resident stem cells are likely sequestered as reserve cells within myocardial niches during the course of embryonic cardiogenesis, although they may also be recruited from external sources, such as bone marrow. As we begin to understand the nature of cardiac-resident stem and progenitor cells using a variety of approaches, it is evident that they possess an identity embedded within their gene regulatory networks that favours cardiovascular lineage potential. In addition to contributing lineage descendants, cardiac stem cells may also be stress sensors, offering trophic cues to other cell types, including cardiomyocytes and vasculature cells, and likely other stem cells and immune cells, during adaptation and repair. This presents numerous possibilities for endogenous cardiac stem and progenitor cells to be used in cell therapies or as targets in heart rejuvenation. In this review, we focus on the epicardium as an endogenous source of multi-potential mesenchymal progenitor cells in development and as a latent source of such progenitors in the adult. We track the origin and plasticity of the epicardium in embryos and adults in both homeostasis and disease. In this context, we ask whether directed activation of epicardium-derived progenitor cells might have therapeutic application.
      PubDate: 2014-04-23
      DOI: 10.3390/jdb2020117
      Issue No: Vol. 2, No. 2 (2014)
  • JDB, Vol. 2, Pages 138-157: Molecular Control of Interdigital Cell Death
           and Cell Differentiation by Retinoic Acid during Digit Development

    • Authors: Martha Díaz-Hernández, Alberto Rios-Flores, René Abarca-Buis, Marcia Bustamante, Jesús Chimal-Monroy
      Pages: 138 - 157
      Abstract: The precise coordination of cell death and cell differentiation during the formation of developing digits is essential for generating properly shaped limbs. Retinoic acid (RA) has a fundamental role in digit development; it promotes or inhibits the molecular expression of several critical genes. This control of gene expression establishes molecular cascades that enable both the commencement of cell death and the inhibition of cell differentiation. In this review, we focus on the antagonistic functions between RA and fibroblast growth factor (FGF) signaling in the control of cell death and between RA and transforming growth factor beta (TGFβ) signaling in the control of cell differentiation.
      PubDate: 2014-04-29
      DOI: 10.3390/jdb2020138
      Issue No: Vol. 2, No. 2 (2014)
  • JDB, Vol. 2, Pages 1-17: The Epicardium and the Development of the
           Atrioventricular Junction in the Murine Heart

    • Authors: Marie Lockhart, Aimee Phelps, Maurice van den Hoff, Andy Wessels
      Pages: 1 - 17
      Abstract: Insight into the role of the epicardium in cardiac development and regeneration has significantly improved over the past ten years. This is mainly due to the increasing availability of new mouse models for the study of the epicardial lineage. Here we focus on the growing understanding of the significance of the epicardium and epicardially-derived cells in the formation of the atrioventricular (AV) junction. First, through the process of epicardial epithelial-to-mesenchymal transformation (epiEMT), the subepicardial AV mesenchyme is formed. Subsequently, the AV-epicardium and epicardially-derived cells (EPDCs) form the annulus fibrosus, a structure important for the electrical separation of atrial and ventricular myocardium. Finally, the AV-EPDCs preferentially migrate into the parietal AV valve leaflets, largely replacing the endocardially-derived cell population. In this review, we provide an overview of what is currently known about the regulation of the events involved in this process.
      PubDate: 2014-03-04
      DOI: 10.3390/jdb2010001
      Issue No: Vol. 2, No. 1 (2014)
  • JDB, Vol. 2, Pages 18-33: Signaling by Retinoic Acid in Embryonic and
           Adult Hematopoiesis

    • Authors: Elena Cano, Laura Ariza, Ramón Muñoz-Chápuli, Rita Carmona
      Pages: 18 - 33
      Abstract: Embryonic and adult hematopoiesis are both finely regulated by a number of signaling mechanisms. In the mammalian embryo, short-term and long-term hematopoietic stem cells (HSC) arise from a subset of endothelial cells which constitute the hemogenic endothelium. These HSC expand and give rise to all the lineages of blood cells in the fetal liver, first, and in the bone marrow from the end of the gestation and throughout the adult life. The retinoic acid (RA) signaling system, acting through the family of nuclear retinoic acid receptors (RARs and RXRs), is involved in multiple steps of the hematopoietic development, and also in the regulation of the differentiation of some myeloid lineages in adults. In humans, the importance of this RA-mediated control is dramatically illustrated by the pathogeny of acute promyelocytic leukemia, a disease produced by a chromosomal rearrangement fusing the RARa gene with other genes. The aberrant fusion protein is able to bind to RARα target gene promoters to actively suppress gene transcription. Lack of function of RARα leads to a failure in the differentiation of promyelocytic progenitors. In this review we have collected the available information about all the phases of the hematopoietic process in which RA signaling is involved, being essential for steps such as the emergence of HSC from the hemogenic endothelium, or modulating processes such as the adult granulopoiesis. A better knowledge of the RA-mediated signaling mechanisms can contribute to the knowledge of the origin of many pathologies of the hematopoietic system and can provide new clinical avenues for their treatment.
      PubDate: 2014-03-17
      DOI: 10.3390/jdb2010018
      Issue No: Vol. 2, No. 1 (2014)
  • JDB, Vol. 2, Pages 34-49: Checking the Pulse of Vitamin A Metabolism and
           Signaling during Mammalian Spermatogenesis

    • Authors: Travis Kent, Michael Griswold
      Pages: 34 - 49
      Abstract: Vitamin A has been shown to be essential for a multitude of biological processes vital for mammalian development and homeostasis. Its active metabolite, retinoic acid (RA), is important for establishing and maintaining proper germ cell development. During spermatogenesis, the germ cells orient themselves in very distinct patterns, which have been organized into stages. There is evidence to show that, in the mouse, RA is needed for many steps during germ cell development. Interestingly, RA has been implicated as playing a role within the same two Stages: VII and VIII, where meiosis is initiated and spermiation occurs. The goal of this review is to outline this evidence, exploring the relevant players in retinoid metabolism, storage, transport, and signaling. Finally, this review will provide a potential model for how RA activity is organized across the murine stages of the spermatogenic cycle.
      PubDate: 2014-03-21
      DOI: 10.3390/jdb2010034
      Issue No: Vol. 2, No. 1 (2014)
  • JDB, Vol. 2, Pages 50-71: Retinoids and Cardiac Development

    • Authors: Stéphane Zaffran, Nicolas Robrini, Nicolas Bertrand
      Pages: 50 - 71
      Abstract: Retinoic acid (RA), a derivative of vitamin A, is involved in signal transduction during vertebrate organogenesis. Retinoids through binding to nuclear receptors called RA receptors (RARs) and retinoid X receptors (RXRs) regulate various processes during cardiogenesis. Deregulated retinoid signaling thus has later consequences leading to cardiac malformations. In this review, we will summarize and discuss our current knowledge on the role of RA signaling during heart development, especially during patterning of the heart fields. We have also integrated recent experiments essential for our understanding of the role of RA signaling during epicardial development and myocardial growth.
      PubDate: 2014-03-21
      DOI: 10.3390/jdb2010050
      Issue No: Vol. 2, No. 1 (2014)
  • JDB, Vol. 1, Pages 186-202: The Epicardium and Coronary Artery Formation

    • Authors: Adriana Pires-Gomes, José Pérez-Pomares
      Pages: 186 - 202
      Abstract: The coronary system is the network of blood vessels that nourishes the heart muscle. After birth, proper coronary blood circulation is required to support heart homeostasis, and altered coronary function frequently leads to myocardial ischemia, infarction and heart failure. The epicardium plays a pivotal role during coronary blood vessel embryonic development, contributing cells to the coronary vasculature, but also secreting diffusible signals that regulate coronary morphogenesis and secondarily impact on ventricular compact myocardium growth. Accordingly, anomalous epicardium development gives rise to the multiple congenital defects of the coronary vascular system and the heart walls. In this review, we will summarize and discuss our current knowledge on the embryogenesis of coronary blood vessels, as related to epicardial development, and attempt to highlight the biomedical relevance of this tissue.
      PubDate: 2013-10-18
      DOI: 10.3390/jdb1030186
      Issue No: Vol. 1, No. 3 (2013)
  • JDB, Vol. 1, Pages 64-81: Development of the Serosal Mesothelium

    • Authors: Nichelle Winters, David Bader
      Pages: 64 - 81
      Abstract: Mesothelia in the adult vertebrate are the simple squamous epithelia covering all coelomic organs and body cavities. Until recently, analysis of the generation and differentiative potential of mesothelia in organogenesis has largely focused on development of visceral mesothelium of the heart; the epicardium and its progenitor, the proepicardium. Here, we review emerging data on the development and differentiation of serosal mesothelium, the covering of the gastrointestinal tract. This literature demonstrates that serosal mesothelium is generated through a completely different mechanism than that seen in the heart suggesting that commitment of progenitors to this cell lineage does not follow a common pathway. The differentiative potential of serosal mesothelium is also discussed in comparison to that observed for progeny of the proepicardium/epicardium. In our review of the literature, we point out gaps in our understanding of serosal mesothelial development and that of mesothelial development as a whole.
      PubDate: 2013-06-26
      DOI: 10.3390/jdb1020064
      Issue No: Vol. 1, No. 2 (2013)
  • JDB, Vol. 1, Pages 82-91: Induction of the Proepicardium

    • Authors: Lisandro Maya-Ramos, James Cleland, Michael Bressan, Takashi Mikawa
      Pages: 82 - 91
      Abstract: The proepicardium is a transient extracardiac embryonic tissue that gives rise to the epicardium and a number of coronary vascular cell lineages. This important extracardiac tissue develops through multiple steps of inductive events, from specification of multiple cell lineages to morphogenesis. This article will review our current understanding of inductive events involved in patterning of the proepicardium precursor field, specification of cell types within the proepicardium and their extension and attachment to the heart.
      PubDate: 2013-07-01
      DOI: 10.3390/jdb1020082
      Issue No: Vol. 1, No. 2 (2013)
  • JDB, Vol. 1, Pages 92-111: Transcriptional Control of Cell Lineage
           Development in Epicardium-Derived Cells

    • Authors: Caitlin Braitsch, Katherine Yutzey
      Pages: 92 - 111
      Abstract: Epicardial derivatives, including vascular smooth muscle cells and cardiac fibroblasts, are crucial for proper development of the coronary vasculature and cardiac fibrous matrix, both of which support myocardial integrity and function in the normal heart. Epicardial formation, epithelial-to-mesenchymal transition (EMT), and epicardium-derived cell (EPDC) differentiation are precisely regulated by complex interactions among signaling molecules and transcription factors. Here we review the roles of critical transcription factors that are required for specific aspects of epicardial development, EMT, and EPDC lineage specification in development and disease. Epicardial cells and subepicardial EPDCs express transcription factors including Wt1, Tcf21, Tbx18, and Nfatc1. As EPDCs invade the myocardium, epicardial progenitor transcription factors such as Wt1 are downregulated. EPDC differentiation into SMC and fibroblast lineages is precisely regulated by a complex network of transcription factors, including Tcf21 and Tbx18. These and other transcription factors also regulate epicardial EMT, EPDC invasion, and lineage maturation. In addition, there is increasing evidence that epicardial transcription factors are reactivated with adult cardiac ischemic injury. Determining the function of reactivated epicardial cells in myocardial infarction and fibrosis may improve our understanding of the pathogenesis of heart disease.
      PubDate: 2013-07-03
      DOI: 10.3390/jdb1020092
      Issue No: Vol. 1, No. 2 (2013)
  • JDB, Vol. 1, Pages 112-125: Epicardium Formation as a Sensor in Toxicology

    • Authors: Peter Hofsteen, Jessica Plavicki, Richard Peterson, Warren Heideman
      Pages: 112 - 125
      Abstract: Zebrafish (Danio rerio) are an excellent vertebrate model for studying heart development, regeneration and cardiotoxicity. Zebrafish embryos exposed during the temporal window of epicardium development to the aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit severe heart malformations. TCDD exposure prevents both proepicardial organ (PE) and epicardium development. Exposure later in development, after the epicardium has formed, does not produce cardiac toxicity. It is not until the adult zebrafish heart is stimulated to regenerate does TCDD again cause detrimental effects. TCDD exposure prior to ventricular resection prevents cardiac regeneration. It is likely that TCDD-induced inhibition of epicardium development and cardiac regeneration occur via a common mechanism. Here, we describe experiments that focus on the epicardium as a target and sensor of zebrafish heart toxicity.
      PubDate: 2013-07-24
      DOI: 10.3390/jdb1020112
      Issue No: Vol. 1, No. 2 (2013)
  • JDB, Vol. 1, Pages 126-140: Left-Right Asymmetrical Development of the

    • Authors: Jan Schlueter, Thomas Brand
      Pages: 126 - 140
      Abstract: The proepicardium (PE) is a cluster of cells that forms on the cardiac inflow tract and gives rise to the epicardium and connective tissue and largely contributes to the coronary vasculature. In many vertebrates, the PE undergoes left-right asymmetrical development. While PE cells and marker genes can be initially found on both sides, only the right-sided PE will fully develop and ultimately deliver cells to the heart. Several signalling inputs, like FGF and BMP signals, are involved in PE induction in the lateral plate mesoderm, as well as during inflow tract formation and, also, control asymmetric PE development. These signalling events will be put into the context of embryonic left-right asymmetry determination. Finally, it will be discussed whether PE development may serve as a readout for asymmetric inflow tract morphogenesis.
      PubDate: 2013-07-26
      DOI: 10.3390/jdb1020126
      Issue No: Vol. 1, No. 2 (2013)
  • JDB, Vol. 1, Pages 141-158: Epicardial Lineages and Cardiac Repair

    • Authors: Manvendra Singh, Jonathan Epstein
      Pages: 141 - 158
      Abstract: The death of cardiac myocytes resulting from myocardial infarction is a major cause of heart failure worldwide. Effective therapies for regenerating lost cardiac myocytes are lacking. Recently, the epicardium has been implicated as a source of inflammatory cytokines, growth factors and progenitor cells that modulate the response to myocardial injury. During embryonic development, epicardially-derived cells have the potential to differentiate into multiple cardiac lineages, including fibroblasts, vascular smooth muscle and potentially other cell types. In the healthy adult heart, epicardial cells are thought to be generally quiescent. However, injury of the adult heart results in reactivation of a developmental gene program in the epicardium, which leads to increased epicardial cell proliferation and differentiation of epicardium-derived cells (EPDCs) into various cardiac lineages. Recent work suggests that epicardial reactivation after injury is accompanied by, and contributes to, a robust inflammatory response. In this review, we describe the current status of research related to epicardial biology in cardiac development and regeneration, highlighting important recent discoveries and ongoing controversies.
      PubDate: 2013-08-26
      DOI: 10.3390/jdb1020141
      Issue No: Vol. 1, No. 2 (2013)
  • JDB, Vol. 1, Pages 159-185: Soluble VCAM-1 Alters Lipid Phosphatase
           Activity in Epicardial Mesothelial Cells: Implications for Lipid Signaling
           During Epicardial Formation

    • Authors: Manjari Ranganathan, Danijela Dokic, Sonia Sterrett, Kathryn Dwyer, Robert Dettman
      Pages: 159 - 185
      Abstract: Epicardial formation involves the attachment of proepicardial (PE) cells to the heart and the superficial migration of mesothelial cells over the surface of the heart. Superficial migration has long been known to involve the interaction of integrins expressed by the epicardium and their ligands expressed by the myocardium; however, little is understood about signals that maintain the mesothelium as it migrates. One signaling pathway known to regulate junctional contacts in epithelia is the PI3K/Akt signaling pathway and this pathway can be modified by integrins. Here, we tested the hypothesis that the myocardially expressed, integrin ligand VCAM-1 modulates the activity of the PI3K/Akt signaling pathway by activating the lipid phosphatase activity of PTEN. We found that epicardial cells stimulated with a soluble form of VCAM-1 (sVCAM-1) reorganized PTEN from the cytoplasm to the membrane and nucleus and activated PTEN’s lipid phosphatase activity. Chick embryonic epicardial mesothelial cells (EMCs) expressing a shRNA to PTEN increased invasion in collagen gels, but only after stimulation by TGFβ3, indicating that loss of PTEN is not sufficient to induce invasion. Expression of an activated form of PTEN was capable of blocking degradation of junctional complexes by TGFβ3. This suggested that PTEN plays a role in maintaining the mesothelial state of epicardium and not in EMT. We tested if altering PTEN activity could affect coronary vessel development and observed that embryonic chick hearts infected with a virus expressing activated human PTEN had fewer coronary vessels. Our data support a role for VCAM-1 in mediating critical steps in epicardial development through PTEN in epicardial cells.
      PubDate: 2013-09-18
      DOI: 10.3390/jdb1020159
      Issue No: Vol. 1, No. 2 (2013)
  • JDB, Vol. 1, Pages 3-19: Evolutionary Origin of the Proepicardium

    • Authors: Elena Cano, Rita Carmona, Ramón Muñoz-Chápuli
      Pages: 3 - 19
      Abstract: The embryonic epicardium and the cardiac mesenchyme derived from it are critical to heart development. The embryonic epicardium arises from an extracardiac progenitor tissue called the proepicardium, a proliferation of coelomic cells located at the limit between the liver and the sinus venosus. A proepicardium has not been described in invertebrates, and the evolutionary origin of this structure in vertebrates is unknown. We herein suggest that the proepicardium might be regarded as an evolutionary derivative from an ancient pronephric external glomerulus that has lost its excretory role. In fact, we previously described that the epicardium arises by cell migration from the primordia of the right pronephric external glomerulus in a representative of the most primitive vertebrate lineage, the lamprey Petromyzon marinus. In this review, we emphasize the striking similarities between the gene expression profiles of the proepicardium and the developing kidneys, as well as the parallelisms in the signaling mechanisms involved in both cases. We show some preliminary evidence about the existence of an inhibitory mechanism blocking glomerular differentiation in the proepicardium. We speculate as to the possibility that this developmental link between heart and kidney can be revealing a phylogenetically deeper association, supported by the existence of a heart-kidney complex in Hemichordates. Finally, we suggest that primitive hematopoiesis could be related with this heart-kidney complex, thus accounting for the current anatomical association of the hematopoietic stem cells with an aorta-gonad-mesonephros area. In summary, we think that our hypothesis can provide new perspectives on the evolutionary origin of the vertebrate heart.
      PubDate: 2013-05-30
      DOI: 10.3390/jdb1010003
      Issue No: Vol. 1, No. 1 (2013)
  • JDB, Vol. 1, Pages 20-31: Role of Prokineticin Receptor-1 in Epicardial
           Progenitor Cells

    • Authors: Thu Nguyen, Adelin Gasser, Canan Nebigil
      Pages: 20 - 31
      Abstract: G protein-coupled receptors (GPCRs) form a large class of seven transmembrane (TM) domain receptors. The use of endogenous GPCR ligands to activate the stem cell maintenance or to direct cell differentiation would overcome many of the problems currently encountered in the use of stem cells, such as rapid in vitro differentiation and expansion or rejection in clinical applications. This review focuses on the definition of a new GPCR signaling pathway activated by peptide hormones, called “prokineticins”, in epicardium-derived cells (EPDCs). Signaling via prokineticin-2 and its receptor, PKR1, is required for cardiomyocyte survival during hypoxic stress. The binding of prokineticin-2 to PKR1 induces proliferation, migration and angiogenesis in endothelial cells. The expression of prokineticin and PKR1 increases during cardiac remodeling after myocardial infarction. Gain of function of PKR1 in the adult mouse heart revealed that cardiomyocyte-PKR1 signaling activates EPDCs in a paracrine fashion, thereby promoting de novo vasculogenesis. Transient PKR1 gene therapy after myocardial infarction in mice decreases mortality and improves heart function by promoting neovascularization, protecting cardiomyocytes and mobilizing WT1+ cells. Furthermore, PKR1 signaling promotes adult EPDC proliferation and differentiation to adopt endothelial and smooth muscle cell fate, for the induction of de novo vasculogenesis. PKR1 is expressed in the proepicardium and epicardial cells derived from mice kidneys. Loss of PKR1 causes deficits in EPDCs in the neonatal mice hearts and kidneys and impairs vascularization and heart and kidney function. Taken together, these data indicate a novel role for PKR1 in heart-kidney complex via EPDCs.
      PubDate: 2013-06-18
      DOI: 10.3390/jdb1010020
      Issue No: Vol. 1, No. 1 (2013)
  • JDB, Vol. 1, Pages 32-46: Epicardial Lineages

    • Authors: Franziska Greulich, Andreas Kispert
      Pages: 32 - 46
      Abstract: The epicardium is the mono-layered epithelium that covers the outer surface of the myocardium from early in cardiac development. Long thought to act merely passively to protect the myocardium from frictional forces in the pericardial cavity during the enduring contraction and expansion cycles of the heart, it is now considered to be a crucial source of cells and signals that direct myocardial growth and formation of the coronary vasculature during development and regeneration. Lineage tracing efforts in the chick, the mouse and the zebrafish unambiguously identified fibroblasts in interstitial and perivascular locations as well as coronary smooth muscle cells as the two major lineages that derive from epithelial-mesenchymal transition and subsequent differentiation from individual epicardial cells. However, controversies exist about an additional endothelial and myocardial fate of epicardial progenitor cells. Here, we review epicardial fate mapping efforts in three vertebrate model systems, describe their conceptual differences and discuss their methodological limitations to reach a consensus of the potential of (pro-)epicardial cells in vitro and in vivo.
      PubDate: 2013-06-21
      DOI: 10.3390/jdb1010032
      Issue No: Vol. 1, No. 1 (2013)
  • JDB, Vol. 1, Pages 47-63: Microsurgical Procedures for Studying the
           Developmental Significance of the Proepicardium and Epicardium in Avian
           Embryos: PE-Blocking, PE-Photoablation, and PE-Grafting

    • Authors: Jörg Männer
      Pages: 47 - 63
      Abstract: The epicardium is the outer skin of the mature vertebrate heart. Its embryonic origin and its possible roles in the developing and mature heart did not receive much recognition during the 19th and most of the 20th century. During the past 25 years, however, the epicardium came into the focus of developmental biology and regenerative medicine. Clinical researchers usually prefer genetically modified mouse models when they want to gain insight into developmental or pathological processes. The story of research on the embryonic epicardium, however, nicely demonstrates the value of non-mammalian species, namely avian species, for elucidating fundamental processes in embryonic and fetal development. Studies on chick and quail embryos have not only led to the identification of the primarily extracardiac source of the epicardium—presently called the proepicardium (PE)—they have also significantly contributed to our current knowledge about the developmental significance of the embryonic epicardium. In this review article, I describe three “classical” microsurgical experiments that have been developed for studying the developmental significance of the PE/epicardium in avian embryos (mechanical PE-blocking, PE-photoablation, orthotopic PE-grafting). Furthermore, I show how these microsurgical experiments have contributed to our current knowledge about the roles of the PE/epicardium in cardiac development. There are still some unsolved aspects in the physiology of the developing epicardium, which may be clarified with the aid of these “classical” microsurgical experiments.
      PubDate: 2013-06-21
      DOI: 10.3390/jdb1010047
      Issue No: Vol. 1, No. 1 (2013)
  • JDB, Vol. 1, Pages 1-2: Developmental Biology — Expanding the

    • Authors: Andy Wessels
      Pages: 1 - 2
      Abstract: Developmental biology is arguably the most exciting field of study within the biological sciences. To elucidate how complex organisms develop from a single cell into a complex organism is a quest that has captured the minds of many great scientists. [...]
      PubDate: 2012-09-25
      DOI: 10.3390/jdb1010001
      Issue No: Vol. 1, No. 1 (2012)
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