Epicardial-Derived Cell Epithelial-to-Mesenchymal Transition and Fate Specification Require PDGF Receptor Signaling

Rationale: In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFR beta is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFR alpha has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development. Objective: To understand the contribution of PDGF receptors in epicardial development and epicardial-derived cell fate determination. Methods and Results: By generating mice with epicardial-specific deletion of the PDGF receptors, we found that epicardial epithelial-to-mesenchymal transition (EMT) was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFR alpha resulted in a specific disruption of cardiac fibroblast development, whereas cVSMC development was unperturbed. Conclusions: Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial-mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial-derived cell fates. (Circ Res. 2011;108:e15-e26.)