Article

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

Leiden University, Leyden, South Holland, Netherlands
Circulation Research (Impact Factor: 11.02). 12/2000; 87(11):969-71. DOI: 10.1161/01.RES.87.11.969
Source: PubMed

ABSTRACT

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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    • "Interestingly, the effect of depletion of LRP2 on the cardiovascular development has never been described in mice, although expression of LRP2 on the mesothelial cells of the Disease Models & Mechanisms @BULLET DMM @BULLET Advance article pericardial cavity has been reported together with expression of LRP2 in the neural crest (Assemat et al., 2005;Fisher and Howie, 2006). Previous studies have consistently shown that the epicardium which arises from the pericardial mesothelium, and neural crest play important roles in the development of different cardiac structures such as the ventricular myocardium, the atrioventricular valves, the coronary arteries, and the distal part of the outflow tract (Gittenberger-de Groot et al., 2000;Gittenberger-de Groot et al., 2012;Poelmann et al., 1998;Waldo et al., 2005;Wessels et al., 2012). We examined in a developmental series the hearts of lrp2 knock out mouse embryos to elucidate a role of LRP2 in cardiac development and to determine which cardiac and/or extra-cardiac cell population is affected by the absence of the protein. "
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    ABSTRACT: Background Lipoprotein-related receptor protein 2 (LRP2) is important for the embryonic neural crest and brain development in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knock out (ko) mice have not yet been investigated.Methods We studied the cardiovascular development of Lrp2 ko mice between embryonic day E10.5 and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2.Results The Lrp2 ko mice display a range of severe cardiovascular abnormalities including aortic arch anomalies, common arterial trunk with coronary anomalies, ventricular septal defects, overriding tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 ko. This explains the absence of the aorto-pulmonary septum leading to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur, however, there are less WT1 positive epicardium derived cells in the ventricular wall as compared to normal coinciding with the myocardial thinning and deep intertrabecular spaces.Conclusions LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.
    Preview · Article · Jan 2016 · Disease Models and Mechanisms
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    • "Avian and mouse embryos with hampered epicardial outgrowth exhibit severe cardiac developmental problems, including a thin myocardial wall and malformation of the coronary vasculature [8] [9] [10] [11] [12], demonstrating the essential role for the epicardium in cardiac development. "
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    ABSTRACT: The transcription factor Wilms' Tumor-1 (WT1) is essential for cardiac development. Deletion of WT1 in mice results in disturbed epicardial and myocardial formation and lack of cardiac vasculature, causing embryonic lethality. Little is known about the role of WT1 in the human fetal heart. Therefore, as a first step, we analyzed the expression pattern of WT1 protein during human cardiac development from week 4 till week 20. WT1 expression was apparent in epicardial, endothelial and endocardial cells in a spatiotemporal manner. The expression of WT1 follows a pattern starting at the epicardium and extending towards the lumen of the heart, with differences in timing and expression levels between the atria and ventricles. The expression of WT1 in cardiac arterial endothelial cells reduces in time, whereas WT1 expression in the endothelial cells of cardiac veins and capillaries remains present at all stages studied. This study provides for the first time a detailed description of the expression of WT1 protein during human cardiac development, which indicates an important role for WT1 also in human cardiogenesis.
    Full-text · Article · Dec 2015 · Journal of Molecular and Cellular Cardiology
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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.
    Full-text · Article · Jan 2015 · Development
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