Although self‐renewal ability of adult mammalian heart has been reported, few pharmacological treatments are known to promote cardiomyocyte regeneration after injury. In this study, we demonstrate that the critical period of stem/progenitor cell‐mediated cardiomyocyte replenishment is initiated within 7 days and saturates on day 10 post‐infarction. Moreover, blocking the inflammatory reaction with COX‐2 inhibitors may also reduce the capability of endogenous stem/progenitor cells to repopulate lost cells. Injection of the COX‐2 product PGE2 enhances cardiomyocyte replenishment in young mice and recovers cell renewal through attenuating TGF‐β1 signaling in aged mice. Further analyses suggest that cardiac stem cells are PGE2‐responsive and that PGE2 may regulate stem cell activity directly through the EP2 receptor or indirectly by modulating its micro‐environment in vivo. Our findings provide evidence that PGE2 holds great potential for cardiac regeneration.
