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Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons

Published:5 April 2022 DOI: 10.1016/j.celrep.2022.110643 PMID: 35385754
Ching Ying Huang,?Martin W Nicholson,?Jyun Yuan Wang,?Chien Yu Ting,?Ming Heng Tsai,?Yu Che Cheng,?Chun Lin Liu,?Darien Z H Chan,?Yi Chan Lee,?Ching Chuan Hsu,?Yu Hung Hsu,?Chiou Fong Yang,?Cindy M C Chang,?Shu Chian Ruan,?Po Ju Lin,?Jen Hao Lin,?Li Lun Chen,?Marvin L Hsieh,?Yuan Yuan Cheng,?Wan Tseng Hsu,?Yi Ling Lin,?Chien Hsiun Chen,?Yu Hsiang Hsu,?Ying Ta Wu,?Timothy A Hacker,?Joseph C Wu,?Timothy J Kamp,?Patrick C H Hsieh

Abstract

In this study, we establish a population-based human induced pluripotent stem cell (hiPSC) drug screening platform for toxicity assessment. After recruiting 1,000 healthy donors and screening for high-frequency human leukocyte antigen (HLA) haplotypes, we identify 13 HLA-homozygous "super donors" to represent the population. These "super donors" are also expected to represent at least 477,611,135 of the global population. By differentiating these representative hiPSCs into cardiomyocytes and neurons we show their utility in a high-throughput toxicity screen. To validate hit compounds, we demonstrate dose-dependent toxicity of the hit compounds and assess functional modulation. We also show reproducible in?vivo drug toxicity results using mouse models with select hit compounds. This study shows the feasibility of using a population-based hiPSC drug screening platform to assess cytotoxicity, which can be used as an innovative tool to study inter-population differences in drug toxicity and adverse drug reactions in drug discovery applications.

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