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.

最近的研究表明，移植 hiPS-CM 是治疗心力衰竭的一种有前途的方法。然而，最佳的临床益处受到了 hiPS-CM 的不成熟性质的阻碍，并且 hiPS-CM 分泌的有助于心肌细胞修复的蛋白质在很大程度上仍未确定。在这里，我们建立了皂素⁺化合物优化诱导系统以在体外产生具有稳定功能属性的hiPS-CM并移植到心力衰竭小鼠中。我们的研究表明，通过减轻心脏重塑和功能障碍，最佳诱导的 hiPS-CM 的治疗效果得到增强，这些有益效果伴随着心肌细胞死亡减少和血管生成增加。此外，最佳诱导的hiPS-CM可以聚集到受伤的心脏并分泌丰富的PDGF-BB。最佳诱导的hiPS-CMs在缺氧损伤的HCMs中的修复作用被PDGF-BB模拟但被PDGF-BB中和抗体抑制，伴随着p-PI3K和p-Akt蛋白表达的改变。与标准诱导的 hiPS-CMs 相比，PI3K/Akt 通路很可能受到化合物诱导的 hiPS-CMs 分泌的 PDGF-BB 的调节，从而实现更持久的心肌修复效果。总之，我们的数据强烈暗示该化合物诱导的 hiPS-CM 通过旁分泌作用促进受伤心脏的恢复。在这个过程中，来自该化合物诱导的 hiPS-CMs 的旁分泌因子 PDGF-BB 减少了异丙肾上腺素诱导的与改善心脏功能相关的不良心脏重塑，这些作用是由 PI3K/Akt 通路介导的，表明最佳的诱导的hiPS-CMs可能作为一种新的有前途的临床应用细胞疗法。我们的数据强烈暗示该化合物诱导的 hiPS-CM 通过旁分泌作用促进受伤心脏的恢复。在这个过程中，来自该化合物诱导的 hiPS-CMs 的旁分泌因子 PDGF-BB 减少了异丙肾上腺素诱导的与改善心脏功能相关的不良心脏重塑，这些作用是由 PI3K/Akt 通路介导的，表明最佳的诱导的hiPS-CMs可能作为一种新的有前途的临床应用细胞疗法。我们的数据强烈暗示该化合物诱导的 hiPS-CM 通过旁分泌作用促进受伤心脏的恢复。在这个过程中，来自该化合物诱导的 hiPS-CMs 的旁分泌因子 PDGF-BB 减少了异丙肾上腺素诱导的与改善心脏功能相关的不良心脏重塑，这些作用是由 PI3K/Akt 通路介导的，表明最佳的诱导的hiPS-CMs可能作为一种新的有前途的临床应用细胞疗法。