PDGFR-β Signaling Regulates Cardiomyocyte Proliferation and Myocardial Regeneration

Cell Rep. 2019 Jul 23;28(4):966-978.e4. doi: 10.1016/j.celrep.2019.06.065.


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.

Keywords: AAV9; Ezh2; PDGFR-β; cardiac repair; cardiomyocyte proliferation; heart regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Proliferation
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Mice, Inbred C57BL
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardium / metabolism*
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Regeneration*
  • Signal Transduction*


  • Enhancer of Zeste Homolog 2 Protein
  • Receptor, Platelet-Derived Growth Factor beta
  • Proto-Oncogene Proteins c-akt