Soft Matrix Promotes Cardiac Reprogramming via Inhibition of YAP/TAZ and Suppression of Fibroblast Signatures

• Published in: Stem cell reports 2020-09, Vol.15 (3), p.612-628
• Main Authors: Kurotsu, Shota, Sadahiro, Taketaro, Fujita, Ryo, Tani, Hidenori, Yamakawa, Hiroyuki, Tamura, Fumiya, Isomi, Mari, Kojima, Hidenori, Yamada, Yu, Abe, Yuto, Murakata, Yoshiko, Akiyama, Tatsuya, Muraoka, Naoto, Harada, Ichiro, Suzuki, Takeshi, Fukuda, Keiichi, Ieda, Masaki
• Format: Article
• Language: English
• Subjects: cardiac reprogramming; mechanotransduction; myocardium; soft matrix; YAP/TAZ
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.07.022

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. [Display omitted] •Hydrogel culture reveals the role of mechanotransduction in cardiac reprogramming•Soft ECM comparable with native myocardium promotes cardiac reprogramming•Soft ECM promotes cardiac reprogramming via YAP/TAZ/fibroblast signaling inhibition•Soft ECM promotes Sendai virus vector-mediated cardiac reprogramming In this article, Ieda and colleagues showed that a soft matrix, which is comparable with native myocardium, efficiently promoted cardiac reprogramming. This soft matrix enhanced cardiac reprogramming via inhibition of integrin, Rho/ROCK, actomyosin, and YAP/TAZ signaling and subsequent suppression of fibroblast programs, which were activated on conventional rigid substrates, thus demonstrating that mechanotransduction plays a critical role in cardiac reprogramming.