Human induced pluripotent stem cell-derived closed-loop cardiac tissue for drug assessment
Junjun Li, Ying Hua, Yuting Liu, Xiang Qu, Jingbo Zhang, Masako Ishida, Noriko Yoshida, Akiko Tabata, Hayato Miyoshi, Mikio Shiba, Shuichiro Higo, Nagako Sougawa, Maki Takeda, Takuji Kawamura, Ryohei Matsuura, Daisuke Okuzaki, Toshihiko Toyofuku, Yoshiki Sawa, Li Liu, Shigeru Miyagawa
Abstract
Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We previously devised a traveling wave (TW) system to promote maturation in 3D cardiac tissue. To align with current drug assessment paradigms (CiPA and JiCSA), necessitating a 2D monolayer cardiac tissue, we integrated the TW system with a multi-electrode array. This gave rise to a hiPSC-derived closed-loop cardiac tissue (iCT), enabling spontaneous TW initiation and swift pacing of cardiomyocytes from various cell lines. The TW-paced cardiomyocytes demonstrated heightened sarcomeric and functional maturation, exhibiting enhanced response to isoproterenol. Moreover, these cells showcased diminished sensitivity to verapamil and maintained low arrhythmia rates with ranolazine-two drugs associated with a low risk of torsades de pointes (TdP). Notably, the TW group displayed increased arrhythmia rates with high and intermediate risk TdP drugs (quinidine and pimozide), underscoring the potential utility of this system in drug assessment applications.