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

Autor:	Huang CY; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Nicholson MW; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Wang JY; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan., Ting CY; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Tsai MH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Cheng YC; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Liu CL; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Chan DZH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Lee YC; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Hsu CC; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Hsu YH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Yang CF; Institute of Applied Mechanics, National Taiwan University, Taipei 106, Taiwan., Chang CMC; Cardiovascular Physiology Core Facility, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA., Ruan SC; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Lin PJ; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Lin JH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Chen LL; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Hsieh ML; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Cardiovascular Physiology Core Facility, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA., Cheng YY; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Hsu WT; School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan., Lin YL; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Chen CH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Hsu YH; Institute of Applied Mechanics, National Taiwan University, Taipei 106, Taiwan., Wu YT; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan., Hacker TA; Cardiovascular Physiology Core Facility, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA., Wu JC; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA., Kamp TJ; Department of Medicine and Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, WI 53705, USA., Hsieh PCH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Department of Medicine and Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Institute of Medical Genomics and Proteomics and Institute of Clinical Medicine, National Taiwan University, Taipei 106, Taiwan. Electronic address: phsieh@ibms.sinica.edu.tw.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Apr 05; Vol. 39 (1), pp. 110643.
DOI:	10.1016/j.celrep.2022.110643
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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