Cell Reports (Apr 2022)
Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons
- 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
Affiliations
- Ching Ying Huang
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Martin W. Nicholson
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Jyun Yuan Wang
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Chien Yu Ting
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Ming Heng Tsai
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Yu Che Cheng
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Chun Lin Liu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Darien Z.H. Chan
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Yi Chan Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Ching Chuan Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Yu Hung Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Chiou Fong Yang
- Institute of Applied Mechanics, National Taiwan University, Taipei 106, Taiwan
- Cindy M.C. Chang
- Cardiovascular Physiology Core Facility, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Shu Chian Ruan
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Po Ju Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Jen Hao Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Li Lun Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Marvin L. Hsieh
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Cardiovascular Physiology Core Facility, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Yuan Yuan Cheng
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Wan Tseng Hsu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Yi Ling Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Chien Hsiun Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
- Yu Hsiang Hsu
- Institute of Applied Mechanics, National Taiwan University, Taipei 106, Taiwan
- Ying Ta Wu
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Timothy A. Hacker
- Cardiovascular Physiology Core Facility, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Joseph C. Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
- Timothy J. Kamp
- Department of Medicine and Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, WI 53705, USA
- Patrick C.H. Hsieh
- 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; Corresponding author
- Journal volume & issue
-
Vol. 39,
no. 1
p. 110643
Abstract
Summary: 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.
