Cardiomyocytes induced from hiPSCs by well-defined compounds have therapeutic potential in heart failure by secreting PDGF-BB

Recent studies have suggested that transplant of hiPS-CMs is a promising approach for treating heart failure.However,the optimally clinical benefits have been hampered by the immature nature of the hiPS-CMs,and the hiPS-CMs-secreted proteins contributing to the repair of cardiomyocytes remain largely unidentified.Here,we established a saponin+compound optimally induced system to generate hiPS-CMs with stable functional attributes in vitro and transplanted in heart failure mice.Our study showed enhanced therapeutic effects of optimally induced hiPS-CMs by attenuating cardiac remodeling and dysfunction,these beneficial effects were concomitant with reduced cardiomyocytes death and increased angiogenesis.Moreover,the optimally induced hiPS-CMs could gathering to the injured heart and secret an abundant PDGF-BB.The reparative effect of the optimally induced hiPS-CMs in the hypoxia-injured HCMs was mimicked by PDGF-BB but inhibited by PDGF-BB neutralizing antibody,which was accompanied by the changed expression of p-PI3K and p-Akt proteins.It is highly possible that the PI3K/Akt pathway is regulated by the PDGF-BB secreted from the compound induced hiPS-CMs to achieve a longer lasting myocardial repair effect compared with the standard induced hiPS-CMs.Taken together,our data strongly implicate that the compound induced hiPS-CMs promote the recovery of injured hearts via paracrine action.In this process,the paracrine factor PDGF-BB derived from the compound induced hiPS-CMs reduces isoproterenol-induced adverse cardiac remodeling,which is associated with improved cardiac function,and these effects are mediated by the PI3K/Akt pathway,suggesting that the optimally induced hiPS-CMs may serve as a new promising cell therapy for clinical applications.