Epicardial Outgrowth Inhibition Leads to Compensatory Mesothelial Outflow Tract Collar and Abnormal Cardiac Septation and Coronary Formation

Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands.
Circulation Research (Impact Factor: 11.02). 12/2000; 87(11):969-71. DOI: 10.1161/01.RES.87.11.969
Source: PubMed


In the present study, we investigated the modulatory role of the epicardium in myocardial and coronary development. Epicardial cell tracing experiments have shown that epicardium-derived cells are the source of interstitial myocardial fibroblasts, cushion mesenchyme, and smooth muscle cells. Epicardial outgrowth inhibition studies show abnormalities of the compact myocardial layer, myocardialization of cushion tissue, looping, septation, and coronary vascular formation. Lack of epicardial spreading is partly compensated by mesothelial outgrowth over the conotruncal region. Heterospecific epicardial transplant is able to partially rescue the myocardial development, as well as septation and coronary formation.

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    • "Epicardium-derived progenitor cells (EPDC) arise following epithelial-to-mesenchymal transition (EMT) (Martinez-Estrada et al., 2010; von Gise et al., 2011), and impact heart development by secretion of paracrine factors or by directly contributing to various cardiac lineages, including vascular endothelial cells (ECs), vascular smooth muscle cells (SMCs) and fibroblasts (Cai et al., 2008; Dettman et al., 1998; Li et al., 2011; Martinez-Estrada et al., 2010; Mikawa and Gourdie, 1996; Tian et al., 2013; Wilm et al., 2005; Zhou et al., 2008). Physical disruption or ablation of the epicardium leads to aberrant vascular plexus formation and myocardial hypoperfusion, highlighting the role of EPDCs in coronary vessel formation (Eralp et al., 2005; Gittenberger-de Groot et al., 2000; Manner et al., 2005). Epicardial cells can also become migratory in the adult, providing a potential source of resident progenitor cells that have the capacity to repopulate damaged cardiac tissue (Lepilina et al., 2006; Limana et al., 2007; Smart et al., 2011; Zhou et al., 2011). "
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    ABSTRACT: An important pool of cardiovascular progenitor cells arises from the epicardium, a single layer of mesothelium lining the heart. Epicardium-derived progenitor cell (EPDC) formation requires epithelial-to-mesenchymal transition (EMT) and the subsequent migration of these cells into the sub-epicardial space. Although some of the physiological signals that promote EMT are understood, the functional mediators of EPDC motility and differentiation are not known. Here, we identify a novel regulatory mechanism of EPDC mobilization. Myocardin-related transcription factor (MRTF)-A and MRTF-B (MKL1 and MKL2, respectively) are enriched in the perinuclear space of epicardial cells during development. Transforming growth factor (TGF)-β signaling and disassembly of cell contacts leads to nuclear accumulation of MRTFs and the activation of the motile gene expression program. Conditional ablation of Mrtfa and Mrtfb specifically in the epicardium disrupts cell migration and leads to sub-epicardial hemorrhage, partially stemming from the depletion of coronary pericytes. Using lineage-tracing analyses, we demonstrate that sub-epicardial pericytes arise from EPDCs in a process that requires the MRTF-dependent motile gene expression program. These findings provide novel mechanisms linking EPDC motility and differentiation, shed light on the transcriptional control of coronary microvascular maturation and suggest novel therapeutic strategies to manipulate epicardium-derived progenitor cells for cardiac repair. © 2015. Published by The Company of Biologists Ltd.
    Development 01/2015; 142(1):21-30. DOI:10.1242/dev.116418 · 6.46 Impact Factor
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    • "We will refer to the EPDCs at the AV junction as AV-EPDCs. The AV-EPDCs derive from the AV-epicardium, which, just like the rest of the epicardium, with the exception of the epicardium found on the outflow tract [19,20], originates from the proepicardium [21–23]. Until a few years ago, our knowledge of the importance of the epicardium in relation to the formation of the coronary vasculature, cardiac fibroblasts, and AV junction was largely based on experimental studies using avian model systems [24–27]. "
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    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.
    03/2014; 2(1):1-17. DOI:10.3390/jdb2010001
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    • "upted epicardial development typically present with a thin compact ventricular wall ( for a review see Wessels and Perez - Pomares ( 2004 ) ) . Likewise , when epicardial development in the developing avian heart is perturbed by micro - surgical procedures , the experimental hearts also are found to have a thin ventricular wall ( Gittenberger - de Groot et al . , 2000 ; Perez - Pomares et al . , 2002 ) . Here we show that the early development of the compact layer precedes the ingrowth of EPDCs into the ventri - cular wall . This indicates that the initial formation of the compact layer does not rely on the migration of EPDCs into the myocardial wall . The subsequent increase in wall thickness does c"
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    ABSTRACT: The importance of the epicardium for myocardial and valvuloseptal development has been well established; perturbation of epicardial development results in cardiac abnormalities, including thinning of the ventricular myocardial wall and malformations of the atrioventricular valvuloseptal complex. To determine the spatiotemporal contribution of epicardially derived cells to the developing fibroblast population in the heart, we have used a mWt1/IRES/GFP-Cre mouse to trace the fate of EPDCs from embryonic day (ED)10 until birth. EPDCs begin to populate the compact ventricular myocardium around ED12. The migration of epicardially derived fibroblasts toward the interface between compact and trabecular myocardium is completed around ED14. Remarkably, epicardially derived fibroblasts do not migrate into the trabecular myocardium until after ED17. Migration of EPDCs into the atrioventricular cushion mesenchyme commences around ED12. As development progresses, the number of EPDCs increases significantly, specifically in the leaflets which derive from the lateral atrioventricular cushions. In these developing leaflets the epicardially derived fibroblasts eventually largely replace the endocardially derived cells. Importantly, the contribution of EPDCs to the leaflets derived from the major AV cushions is very limited. The differential contribution of EPDCs to the various leaflets of the atrioventricular valves provides a new paradigm in valve development and could lead to new insights into the pathogenesis of abnormalities that preferentially affect individual components of this region of the heart. The notion that there is a significant difference in the contribution of epicardially and endocardially derived cells to the individual leaflets of the atrioventricular valves has also important pragmatic consequences for the use of endocardial and epicardial cre-mouse models in studies of heart development.
    Developmental Biology 04/2012; 366(2):111-24. DOI:10.1016/j.ydbio.2012.04.020 · 3.55 Impact Factor
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