Soft Matrix Promotes Cardiac Reprogramming via Inhibition of YAP/TAZ and Suppression of Fibroblast Signatures
Soft Matrix Promotes Cardiac Reprogramming via Inhibition of YAP/TAZ and Suppression of Fibroblast Signatures
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DOI：
10.1016/j.stemcr.2020.07.022
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发表时间：
2020-09-08
影响因子：
5.9
通讯作者：
Ieda, Masaki
中科院分区：
文献类型：
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作者：
Kurotsu, Shota;Sadahiro, Taketaro;Ieda, Masaki
直接心脏重编程在再生医学中具有巨大的潜力。然而，它仍然是低效的，并且体外生成的诱导心肌细胞（iCMs）比体内生成的心肌细胞更不成熟，这表明未定义的外部因素可能调节心脏重编程。先前的体外研究主要使用硬聚苯乙烯培养皿，但底物硬度对心脏重编程的影响尚不清楚。因此，我们开发了一种基于基质的水凝胶培养系统，以确定基质刚度和机械转导在心脏重编程中的作用。我们发现与天然心肌相当的软基质提高了心脏重编程的效率和质量。从机制上讲，软基质通过抑制整合素、Rho/ROCK、肌动球蛋白和YAP/TAZ信号和抑制成纤维细胞程序来增强心脏重编程，这些程序在刚性基质上被激活。软底物通过抑制YAP/TAZ进一步增强了仙台病毒载体的心脏重编程，将重编程效率提高了15%左右。因此，机械转导可以为改善心脏重编程提供新的靶点。
Direct cardiac reprogramming holds great potential for regenerative medicine. However, it remains inefficient, and induced cardiomyocytes (iCMs) generated in vitro are less mature than those in vivo, suggesting that undefined extrinsic factors may regulate cardiac reprogramming. Previous in vitro studies mainly used hard polystyrene dishes, yet the effect of substrate rigidity on cardiac reprogramming remains unclear. Thus, we developed a Matrigel-based hydrogel culture system to determine the roles of matrix stiffness and mechanotransduction in cardiac reprogramming. We found that soft matrix comparable with native myocardium promoted the efficiency and quality of cardiac reprogramming. Mechanistically, soft matrix enhanced cardiac reprogramming via inhibition of integrin, Rho/ROCK, actomyosin, and YAP/TAZ signaling and suppression of fibroblast programs, which were activated on rigid substrates. Soft substrate further enhanced cardiac reprogramming with Sendai virus vectors via YAP/TAZ suppression, increasing the reprogramming efficiency up to similar to 15%. Thus, mechanotransduction could provide new targets for improving cardiac reprogramming.