The Role of the Epicardium in the Formation of the Cardiac Valves in the Mouse
In recent years, insights into the role of the epicardium in cardiac development have significantly changed. An important contribution to this increasing knowledge comes from the availability of mouse models that facilitate the study of the fate of the epicardial cell lineage and that allow epicardial-specific manipulation of expression of genes involved in regulation of epicardial cell behavior. In this contribution we will discuss our growing understanding of the role of the epicardium and epicardially derived cells in the formation of the atrioventricular valve leaflets. We will illustrate how epicardially derived cells specifically contribute to the development of the leaflets that derive from the lateral atrioventricular cushions, and we will discuss the role of Bmp signaling, through the Bmp receptor BmpR1A/Alk3, in the regulation of the preferentially migration of EPDCs into the parietal AV valve leaflets.
KeywordsEpicardium Valves Bmp2 Bmp4 Alk3
20.1.1 The AV Valves and Their Leaflets
20.1.2 The Epicardium and Epicardially Derived Cells (EPDCs)
In the mouse, epicardial development starts around embryonic day 9.5 (ED9.5) when the proepicardium, a heterogeneous cluster of cells, can be seen as a “cauliflower-like” mesothelial structure at the inferior margin of the cardiac sinus venosus at the venous pole of the heart. Around ED10, proepicardial cells reach and attach to the myocardium. Subsequently, they migrate out over the surface of the developing heart, ultimately covering the heart entirely. As a result of an epicardial epithelial-to-mesenchymal transition (epiEMT), epicardially derived cells (EPDC) are generated that migrate into the sub-epicardial space and into the underlying myocardium. Over the last 15 years or so, a series of cell fate studies in avian and murine models have been published reporting that EPDCs can, or have the potential to, differentiate in multiple cell types including coronary smooth muscle cells, interstitial fibroblasts , coronary endothelium, and potentially cardiomyocytes [6, 7, 8, 9]. It is important to note that the contribution of EPDCs to the coronary endothelium and myocardium remains controversial.
20.1.3 The Contribution of EPDCs to the Developing AV Valves
20.2 The Role of Bmp Signaling in Regulating the Contribution of EPDC to the AV Valves
20.2.1 Epicardial-Specific Deletion of the Bmp Receptor BmpR1A/Alk3 Leads to Disruption of AV Junction Development
20.2.3 Future Direction and Clinical Implications
Myxomatous valve disease is generally considered an acquired disease, often observed in patients with mitral valve prolapse. The observed myxomatous changes in the leaflets of the postnatal Wt1-cre;Alk3 mice, however, are associated with a reduced influx of EPDCs within those leaflets during embryonic development. We therefore propose that perturbation in the norm al development of EPDCs in the AV junction might play the role in the etiology of myxomatous valve degen eration in human heart disease.
The authors would like to acknowledge the financial support by NIH grants P30 GM103342 (A.W.), UL1RR029882 and UL1TR000062 (A.W.), R01HL033756 (A.W.) American Heart Association Grant-in-Aid 13GRNT16220004 (A.W.), American Heart Association Predoctoral grant 12PRE11340000 (M.M.L.), European Community’s Sixth Framework Program Grant LSHM-CT-2005-018630 (MJBvdH), and Netherlands Heart Foundation Grant 1996M002 (MJBvdH).
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