Regulation of Cardiac Fibroblast and Coronary Vascular Smooth Muscle Development by Platelet Derived Growth Factor Receptors

Coronary vascular smooth muscle cells (cVSMC) and cardiac fibroblasts are essential for coronary artery development and are important mediators of myocardial pathogenesis. These cells form when a subset of epicardial cells undergoes an epithelial-to-mesenchymal transition (EMT) and migrates into the myocardium. The pathways and mechanisms regulating epicardial derived cell (EPDC) development remain largely unknown. Using mice with epicardial specific deletions of the PDGF receptors, I discovered that these receptors control EPDC fate and epicardial EMT. I demonstrated that each receptor was required for development of a unique epicardial derivative, PDGFRα for cardiac fibroblasts and PDGFRβ for cVSMC. I also found that deletion of both PDGF receptors led to a complete loss of EPDCs caused by a failure in cell exit from the epicardium. This defect resulted from decreased expression of genes involved in the EMT process and continued epithelial gene expression. Finally, I showed that Sox9, an SRY-related transcription factor, is a critical downstream mediator of PDGF signaling. This body of work establishes PDGF signaling as a key EMT regulatory pathway and suggests a novel role for Sox9 in regulating EPDC development.