PDGFR-β Signaling Regulates Cardiomyocyte Proliferation and Myocardial Regeneration

Platelet-derived growth factor receptor (PDGFR) signaling is involved in proliferation and survival in a wide array of cell types. The role of PDGFR signaling in heart regeneration is still unknown. We find that PDGFR-beta signaling decreases in myocardium with age and that conditional activation PDGFR-beta in cardiomyocytes promotes heart regeneration. Employing RNA sequencing, we show that the enhancer of zeste homolog 2 (Ezh2) can be upregulated by PDGFR-beta signaling in primary cardiomyocytes. Conditional knockout of Ezh2 blocks cardiomyocyte proliferation and H3K27me3 modification during neonatal heart regeneration with Ink4a/Arf upregulation, even in mice with myocyte-specific conditional activation of PDGFR-beta. We also show that PDGFR-beta controls EZH2 expression via the phosphatidylinositol 3-kinase (PI3K)/p-Akt pathway in cardiomyocytes. Gene therapy with adeno-associated virus serotype 9 (AAV9) encoding activated PDGFR-beta enhances adult heart regeneration and systolic function. Our data demonstrate that the PDGFR-beta/EZH2 pathway is critical for promoting cardiomyocyte proliferation and heart regeneration, providing a potential target for cardiac repair.