Growing studies have demonstrated that the adult mammalian heart preserves a self-renewal capacity and resides various stem/progenitor cell populations. Also, approximately 20% of cardiomyocytes are replenished by endogenous stem/progenitor cells in the peri-infarct border zone after myocardial infarction (MI) in mice (Hsieh et al. 2007). Interestingly, a recent study by Senyo et al. reported that ~20% of pre-existing cardiomyocytes at the border zone undergo cell cycle although among them, only 3.2% of cells complete the cell division (Senyo et al. 2013). These results imply that the majority of replenished cardiomyocytes may be originated from the endogenous stem/progenitor cells. Nevertheless, a therapy promoting endogenous stem cells to repair injury after MI, including systemic delivery of drugs, is still lacking. It also remains unclear the most critical time period to activate the stem cell-driven cardiomyocyte replenishment. Answers to these questions will offer opportunities for developing new de novo treatments.
　　In this study, we used the cardiac specific tamoxifen-inducible Cre-LoxP MerCreMer/ZEG (M/Z) transgenic mice to delineate the underlying mechanism initiating stem/progenitor cell-modulated cardiac repair and to investigate the regenerative efficiency in young and aged mice. Furthermore, we aimed to identify a pharmacological intervention that improves the cardiac repair efficiency after MI. We showed 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 rejuvenation and regeneration.