Role And Mechanism Of Human Embryonic Stem Cell-derived Cardiovascular Progenitors On Acute Myocardial Infarcted Hearts

Objectives: Myocardial infarction(MI)and the resulting heart failure(HF)are a major cause of morbidity and mortality worldwide.Cumulated evidence suggests that modulation of the inflammatory response during the early phase of MI improves infarct repair,however,clinically useful approaches targeting the modulation of inflammation towards the healing process are lacking.Human embryonic stem cell-derived cardiovascular progenitor cells(h ESC-CVPCs)improve cardiac function of rodent infarcted hearts when implanted during the subacute stage of ischemia/reperfusion(I/R)hearts and shows safety in clinical trials.Using a nonhuman primate(NHP)model of myocardial infarction,it is recently reported that human pluripotent stem cell-derived cardiovascular progenitor cells(h PSC-CVPCs)significantly improve cardiac function 4 weeks after the transplantation,the rapid disappearance of cells after transplantation suggests that this cardiac repair is caused by the paracrine effect of h ESC-CVPCs.However,little is known about the paracrine effects and effect of h ESC-CVPCs on the inflammatory response during the early phase of MI and the contribution of such effect to the cardioprotection.This study aims to investigate the cardioprotective effects of h ESC-CVPCs on cardiac function in acute myocardial infarction and explore the mechanism.Methods and Results: Injection of h ESC-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,h ESC-CVPCs modulated cardiac macrophages towards a reparative phenotype in the infarcted hearts and such modulation was further confirmed in vitro using h ESC-CVPC-conditioned medium(h CVPC-Cd M).Through protein analysis of h ESC-CVPCs cell supernatant,we found that h ESC-CVPCs expressed and secreted a large number of STAT6 activators IL-4 and IL-13.Simultaneously,through signaling pathway screening,we found that STAT6 was activated in h CVPC-Cd M treated macrophages in vitro and in h ESC-CVPC-implanted MI hearts,resulting in the polarization of macrophages towards a reparative phenotype in the post-MI hearts.When macrophage STAT6 is knocked out,the modulation of h ESC-CVPCs on macrophage polarization disappears.Besides,h ESC-CVPC-mediated modulation on macrophages and cardioprotection were abolished in STAT6-deficient MI mice.Conclusions: These results demonstrate,for the first time,that the modulation of macrophage polarization by h ESC-CVPCs plays a significant role in reducing cardiomyocytes apoptosis,increasing angiogenesis and improving cardiac function after myocardial infarction via their paracrine effect-activated STAT6 in macrophages.These findings provide new insight into the mechanism of micro-environmental regulation of stem cell-based therapy during acute MI and suggest therapeutic potential by modulating macrophage polarization in AMI for the infarct healing.