Engineered three-dimensional cardiac tissues maturing in a rotating wall vessel bioreactor remodel diseased hearts in rats with myocardial infarction
Taro Nakazato, Takuji Kawamura, Toshimasa Uemura, Li Liu, Junjun Li, Masao Sasai, Akima Harada, Emiko Ito, Hiroko Iseoka, Köichi Toda, Yoshiki Sawa, Shigeru Miyagawa
Abstract
A rotating wall vessel (RWV) bioreactor was constructed for growing massive functional cardiac constructs to recover the function of a distressed rat heart. Three-dimensional cardiac tissues were engineered by seeding human-induced pluripotent stem cell-derived cardiomyocytes on poly(lactic-co-glycolic acid) fiber sheets (3D-hiPSC-CTs) and cultured in the RWV bioreactor (RWV group) or under static conditions (control group). The tissues were transplanted into a myocardial infarction nude rat model, and cardiac performance was evaluated. In the RWV group, cell viability and contractile and electrical properties significantly improved, mature cardiomyocytes were observed, and mechanical stress-related mediators of mammalian target of rapamycin signaling were upregulated compared with those of the control. Four weeks post-transplantation, tissue survival and left ventricular ejection fraction significantly improved in the RWV group. Hence, dynamic culture in an RWV bioreactor could provide a superior culture environment for improved performance of 3D-hiPSC-CTs, providing a means for functional cardiomyogenesis in myocyte-loss heart failure.