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-β signaling decreases in myocardium with age and that conditional activation PDGFR-β in cardiomyocytes promotes heart regeneration. Employing RNA sequencing, we show that the enhancer of zeste homolog 2 (Ezh2) can be upregulated by PDGFR-β 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-β. We also show that PDGFR-β 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-β enhances adult heart regeneration and systolic function. Our data demonstrate that the PDGFR-β/EZH2 pathway is critical for promoting cardiomyocyte proliferation and heart regeneration, providing a potential target for cardiac repair.

血小板衍生的生长因子受体（PDGFR）信号传导参与多种细胞类型的增殖和存活。PDGFR信号传导在心脏再生中的作用仍然未知。我们发现，PDGFR-β信号随着年龄的增长而在心肌中减少，并且心肌细胞中的条件激活PDGFR-β促进心脏再生。利用RNA测序，我们发现zeste同源2（Ezh2）的增强子可以被PDGFR-β信号在原代心肌细胞中上调。有条件的敲除Ezh2可以抑制Ink4a / Arf在新生儿心脏再生过程中的心肌细胞增殖和H3K27me3修饰甚至在具有PDGFR-β的肌细胞特异性条件激活的小鼠中也上调。我们还显示，PDGFR-β通过心肌细胞中的磷脂酰肌醇3激酶（PI3K）/ p-Akt途径控制EZH2表达。编码激活的PDGFR-β的腺相关病毒血清型9（AAV9）的基因治疗可增强成年心脏的再生和收缩功能。我们的数据表明，PDGFR-β/ EZH2途径对于促进心肌细胞增殖和心脏再生至关重要，为心脏修复提供了潜在靶点。