Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.
Cells. 2023 Aug 22;12(17):2121. doi: 10.3390/cells12172121.
Cardiomyocyte loss following myocardial infarction cannot be addressed with current clinical therapies. Cell therapy with induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a potential approach to replace cardiomyocyte loss. However, engraftment rates in pre-clinical studies have been low, highlighting a need to refine current iPSC-CM technology. In this study, we demonstrated that inducing Yes-associated protein (YAP) by genetic and pharmacological approaches resulted in increased iPSC-CM proliferation and reduced apoptosis in response to oxidative stress. Interestingly, iPSC-CM maturation was differently affected by each strategy, with genetic activation of YAP resulting in a more immature cardiomyocyte-like phenotype not witnessed upon pharmacological YAP activation. Overall, we conclude that YAP activation in iPSC-CMs enhances cell survival and proliferative capacity. Therefore, strategies targeting YAP, or its upstream regulator the Hippo signalling pathway, could potentially be used to improve the efficacy of iPSC-CM technology for use as a future regenerative therapy in myocardial infarction.
心肌梗死后的心肌细胞损失无法通过当前的临床治疗方法解决。诱导多能干细胞衍生的心肌细胞（iPSC-CMs）的细胞治疗是一种替代心肌细胞损失的潜在方法。然而，临床前研究中的植入率一直很低，这凸显了需要改进当前的 iPSC-CM 技术。在这项研究中，我们证明了通过遗传和药理学方法诱导 Yes 相关蛋白（YAP）会导致 iPSC-CM 在氧化应激下增殖增加和凋亡减少。有趣的是，每种策略对 iPSC-CM 成熟的影响不同，遗传激活 YAP 导致更不成熟的心肌细胞样表型，而不是在药理学激活 YAP 时观察到的表型。总的来说，我们得出结论，YAP 在 iPSC-CMs 中的激活增强了细胞的存活和增殖能力。因此，靶向 YAP 或其上游调节 Hippo 信号通路的策略可能可用于提高 iPSC-CM 技术的疗效，作为心肌梗死的未来再生治疗方法。
