Human Embryonic Stem Cell-Derived Cardiovascular Progenitors Repair Infarcted Hearts through Modulation of Macrophages via Activation of STAT6

Aims: Human embryonic stem cell derived-cardiovascular progenitor cells (hESC-CVPCs) are a promising cell source for cardiac repair, while the underlying mechanisms need to be elucidated. We recently observed cardioprotective effects of hPSC-CVPCs in infarcted nonhuman primates, but their effects on inflammation during early phase of myocardial infarction (MI) and the contribution of such effect to the cardioprotection is unclear. Results: Injection of hESC-CVPCs into acutely infarcted myocardium significantly ameliorated the functional worsening and scar formation, concomitantly with reduced inflammatory reactions and cardiomyocyte apoptosis as well as increased vascularization. Moreover, hESC-CVPCs modulated cardiac macrophages towards a reparative phenotype in the infarcted hearts and such modulation was further confirmed in vitro using hESC-CVPC-conditioned medium (hCVPC-CdM) and highly contained IL-4/IL-13. Furthermore, STAT6 was activated in hCVPC-CdM- and IL-4/IL-13-treated macrophages in vitro and in hESC-CVPC-implanted MI hearts, resulting in the polarization of macrophages towards a reparative phenotype in the post-MI hearts. However, hESC-CVPC-mediated modulation on macrophages and cardioprotection were abolished in STAT6-deficient MI mice. Innovation: This is the first report about the immunoregulatory role played by hESC-CVPCs on the macrophage polarization in the infarcted hearts, its importance for infarct repair and the underlying signaling pathway. The findings provide new insight into the mechanism of micro-environmental regulation of stem cell-based therapy during acute MI. Conclusions: Modulation of macrophage polarization by hESC-CVPCs plays a significant role in blunting the worsening of heart function and reducing scar formation via their paracrine effect-activated STAT6, suggesting therapeutic potential by modulating macrophage polarization in acute MI for the infarct healing.