Role of the Epicardium in Valve Development and Valve Disease

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In this project we aim to determine the role of epicardially-derived cells (EPDCs) in the formation of the atrioventricular (AV) valves and to investigate their potential role in the pathogenesis of myxomatous valve disease (MVD). A few years ago, we published a study in which we described how EPDCs at the atrioventricular (AV) junction contribute to a specific set of leaflets of the AV valves. To obtain insight into how these events are regulated, we initially focused on growth factor signaling through the Bone Morphogenetic Protein (BMP) pathway. We deleted the BMP receptor ALK3/BMPR1A from the epicardial cell lineage using the epicardial-specific WT1cre mouse. We observed that this led to abnormalities at the AV junction, including a significant decrease in the number of AV-EPDCs in the lateral valve leaflets. We also found that, after birth, the valves developed a myxomatous valve phenotype, reminiscent of that being observed in patients suffering MVD. Deleting the transcription factor SOX9 from the epicardial cell lineage led to similar results. The goals of this project are to determine the mechanisms regulating the migration of AV- EPDCs into the parietal AV valve leaflet, to establish how AV-EPDCs regulate AV valve development, and to elucidate their role in the pathogenesis of mitral valve disease.