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Soft Matrix Promotes Cardiac Reprogramming via Inhibition of YAP/TAZ and Suppression of Fibroblast Signatures.
Stem Cell Reports ( IF 5.9 ) Pub Date : 2020-08-27 , DOI: 10.1016/j.stemcr.2020.07.022
Shota Kurotsu 1 , Taketaro Sadahiro 2 , Ryo Fujita 3 , Hidenori Tani 1 , Hiroyuki Yamakawa 1 , Fumiya Tamura 1 , Mari Isomi 2 , Hidenori Kojima 1 , Yu Yamada 2 , Yuto Abe 2 , Yoshiko Murakata 2 , Tatsuya Akiyama 4 , Naoto Muraoka 1 , Ichiro Harada 5 , Takeshi Suzuki 6 , Keiichi Fukuda 1 , Masaki Ieda 2
Affiliation  

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 ∼15%. Thus, mechanotransduction could provide new targets for improving cardiac reprogramming.



中文翻译:

软基质通过抑制YAP / TAZ和抑制成纤维细胞签名来促进心脏重编程。

直接心脏重编程在再生医学方面具有巨大潜力。然而,它仍然是低效的,体外产生的诱导心肌细胞(iCM)比体内产生的成熟细胞还不成熟,这表明不确定的外在因素可能会调节心脏的重编程。先前的体外研究主要使用硬质聚苯乙烯餐具,但基质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Matrigel的水凝胶培养系统,以确定基质硬度和机械转导在心脏重编程中的作用。我们发现可与天然心肌媲美的软基质提高了心脏重编程的效率和质量。从机制上讲,软基质通过抑制整联蛋白,Rho / ROCK,放线菌素和YAP / TAZ信号转导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。软质底物通过抑制YAP / TAZ进一步增强了仙台病毒载体的心脏重编程,将重编程效率提高到约15%。因此,机械转导可以为改善心脏重编程提供新的目标。

更新日期:2020-08-27
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