Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and fibroblasts

Kiyoshi Tadano; Shigeru Miyagawa; Maki Takeda; Yoshinari Tsukamoto; Katsuyuki Kazusa; Kazuhiko Takamatsu; Mitsuru Akashi; Yoshiki Sawa

doi:10.1016/j.omtm.2021.05.007

Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and fibroblasts

Mol Ther Methods Clin Dev. 2021 May 21:22:338-349. doi: 10.1016/j.omtm.2021.05.007. eCollection 2021 Sep 10.

Authors

Kiyoshi Tadano¹, Shigeru Miyagawa², Maki Takeda², Yoshinari Tsukamoto³, Katsuyuki Kazusa¹, Kazuhiko Takamatsu¹, Mitsuru Akashi³, Yoshiki Sawa²

Affiliations

¹ Drug Safety Research Labs, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan.
² Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
³ Building Block Science Joint Research Chair, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Three-dimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues. We previously developed a simple method to generate 3D tissue in a short period by coating the cell surfaces with extracellular matrix proteins. We hypothesized that this 3D cardiac tissue could be used for simultaneous evaluation of drug-induced repolarization and contractility. In the present work, we examined the effects of several compounds with different mechanisms of action by cell motion imaging. Consequently, human ether-a-go-go-related gene (HERG) channel blockers with high arrhythmogenic risk caused prolongation of contraction-relaxation duration and arrhythmia-like waveforms. Positive inotropic drugs, which increase intracellular Ca²⁺ levels or myocardial Ca²⁺ sensitivity, caused an increase in maximum contraction speed (MCS) or average deformation distance (ADD) (ouabain, 138% for MCS at 300 nM; pimobendane, 132% for ADD at 3 μM). For negative inotropic drugs, verapamil reduced both MCS and ADD (61% at 100 nM). Thus, this 3D cardiac tissue detected the expected effects of various cardiovascular drugs, suggesting its usefulness for cardiotoxicity evaluation.

Keywords: 3D cardiac tissue; cardiac contractility; cardiomyocytes; cardiotoxicity; human induced pluripotent stem cells.