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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:
Published: April 2022
AI Article Synopsis
* By differentiating these hiPSCs into cardiomyocytes and neurons, we conducted high-throughput toxicity screenings and validated our findings through dose-dependent toxicity assessments and functional modulation.
* Our research demonstrated that this population-based hiPSC platform is a practical approach for studying drug toxicity, helping illuminate differences across populations and enhancing drug discovery processes.
Article 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.
