Special Issue "Epicardial Development and Cardiovascular Disease"

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A special issue of Journal of Developmental Biology (ISSN 2221-3759).

Deadline for manuscript submissions: closed (1 May 2013)

Special Issue Editors

Guest Editor
Prof. Dr. Thomas Brand (Website)

National Heart & Lung Institute, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
Interests: heart development; proepicardial development; left-right asymmetry; cardiac pacemaker development; popeye genes
Guest Editor
Dr. Maurice van den Hoff (Website)

Academic Medical Center, Dept Anatomy, Embryology & Physiology, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands
Interests: cardiovascular development; epicardium development; myocardium formation; cell signalling; BMP signalling; molecular biology; transgenic mice; congenital cardiac abnormalities

Special Issue Information

Dear Colleagues,

The proepicardium is an embryonic structure, which develops at the venous pole and gives rise to the epicardium and cells of the cardiac interstitium (fibroblast and smooth muscle cells). Its contribution to the endothelium is under intense debate and there may be even species-specific differences. The epicardium has an important role later in development as a source of growth signals, which will stimulate the expansion of the ventricular wall in order to provide sufficient cardiac output and to match the demands of the growing embryo. The epicardium has recently also received significant attention because of its involvement in cardiac regeneration, which has been mainly studied in the zebrafish and murine model systems. In the mammalian heart there is strong evidence that the epicardium of the adult heart is a source for cardiac stem cells, possibly involved in wound healing and scar formation in response to injury. Several different model systems have been employed in the past years including cyclostomes, zebrafish, Xenopus, chicken and mice and this special issue of the Journal of Developmental Biology will provide a comprehensive overview of the current standing of this research field. Leading experts have agreed to contribute review articles on this exciting topic. Research papers on epicardial development and the role of the epicardium in cardiac regeneration are welcome contributions to this special issue.

Prof. Thomas Brand
Dr. Maurice van den Hoff
Guest Editor

Submission

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Published Papers (15 papers)

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Research

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Open AccessArticle The Epicardium in the Embryonic and Adult Zebrafish
J. Dev. Biol. 2014, 2(2), 101-116; doi:10.3390/jdb2020101
Received: 8 February 2014 / Revised: 24 February 2014 / Accepted: 26 February 2014 / Published: 11 April 2014
Cited by 3 | PDF Full-text (1573 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessArticle Soluble VCAM-1 Alters Lipid Phosphatase Activity in Epicardial Mesothelial Cells: Implications for Lipid Signaling During Epicardial Formation
J. Dev. Biol. 2013, 1(2), 159-185; doi:10.3390/jdb1020159
Received: 2 May 2013 / Revised: 12 July 2013 / Accepted: 23 August 2013 / Published: 18 September 2013
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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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)

Review

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Open AccessReview Epicardial Origin of Resident Mesenchymal Stem Cells in the Adult Mammalian Heart
J. Dev. Biol. 2014, 2(2), 117-137; doi:10.3390/jdb2020117
Received: 13 January 2014 / Revised: 8 April 2014 / Accepted: 9 April 2014 / Published: 23 April 2014
Cited by 6 | PDF Full-text (1221 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Epicardium-Derived Heart Repair
J. Dev. Biol. 2014, 2(2), 84-100; doi:10.3390/jdb2020084
Received: 27 December 2013 / Revised: 24 February 2014 / Accepted: 3 April 2014 / Published: 10 April 2014
Cited by 2 | PDF Full-text (255 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview The Epicardium and the Development of the Atrioventricular Junction in the Murine Heart
J. Dev. Biol. 2014, 2(1), 1-17; doi:10.3390/jdb2010001
Received: 15 January 2014 / Revised: 19 February 2014 / Accepted: 26 February 2014 / Published: 4 March 2014
Cited by 3 | PDF Full-text (1016 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview The Epicardium and Coronary Artery Formation
J. Dev. Biol. 2013, 1(3), 186-202; doi:10.3390/jdb1030186
Received: 8 July 2013 / Revised: 25 September 2013 / Accepted: 2 October 2013 / Published: 18 October 2013
Cited by 2 | PDF Full-text (342 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Epicardial Lineages and Cardiac Repair
J. Dev. Biol. 2013, 1(2), 141-158; doi:10.3390/jdb1020141
Received: 14 June 2013 / Revised: 8 August 2013 / Accepted: 9 August 2013 / Published: 26 August 2013
Cited by 1 | PDF Full-text (1106 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Left-Right Asymmetrical Development of the Proepicardium
J. Dev. Biol. 2013, 1(2), 126-140; doi:10.3390/jdb1020126
Received: 30 May 2013 / Revised: 15 July 2013 / Accepted: 22 July 2013 / Published: 26 July 2013
PDF Full-text (295 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Epicardium Formation as a Sensor in Toxicology
J. Dev. Biol. 2013, 1(2), 112-125; doi:10.3390/jdb1020112
Received: 27 May 2013 / Revised: 12 July 2013 / Accepted: 15 July 2013 / Published: 24 July 2013
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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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Transcriptional Control of Cell Lineage Development in Epicardium-Derived Cells
J. Dev. Biol. 2013, 1(2), 92-111; doi:10.3390/jdb1020092
Received: 16 May 2013 / Revised: 19 June 2013 / Accepted: 20 June 2013 / Published: 3 July 2013
Cited by 4 | PDF Full-text (366 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Induction of the Proepicardium
J. Dev. Biol. 2013, 1(2), 82-91; doi:10.3390/jdb1020082
Received: 4 June 2013 / Revised: 19 June 2013 / Accepted: 19 June 2013 / Published: 1 July 2013
Cited by 2 | PDF Full-text (327 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Development of the Serosal Mesothelium
J. Dev. Biol. 2013, 1(2), 64-81; doi:10.3390/jdb1020064
Received: 3 May 2013 / Revised: 13 June 2013 / Accepted: 19 June 2013 / Published: 26 June 2013
Cited by 1 | PDF Full-text (1068 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Microsurgical Procedures for Studying the Developmental Significance of the Proepicardium and Epicardium in Avian Embryos: PE-Blocking, PE-Photoablation, and PE-Grafting
J. Dev. Biol. 2013, 1(1), 47-63; doi:10.3390/jdb1010047
Received: 9 May 2013 / Revised: 13 June 2013 / Accepted: 14 June 2013 / Published: 21 June 2013
Cited by 1 | PDF Full-text (879 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Role of Prokineticin Receptor-1 in Epicardial Progenitor Cells
J. Dev. Biol. 2013, 1(1), 20-31; doi:10.3390/jdb1010020
Received: 27 April 2013 / Revised: 5 June 2013 / Accepted: 8 June 2013 / Published: 18 June 2013
Cited by 1 | PDF Full-text (484 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)
Open AccessReview Evolutionary Origin of the Proepicardium
J. Dev. Biol. 2013, 1(1), 3-19; doi:10.3390/jdb1010003
Received: 11 April 2013 / Revised: 13 May 2013 / Accepted: 17 May 2013 / Published: 30 May 2013
Cited by 3 | PDF Full-text (992 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epicardial Development and Cardiovascular Disease)

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