Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons
Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons
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DOI：
10.1016/j.celrep.2022.110643
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发表时间：
2022-04-05
期刊：
影响因子：
8.8
通讯作者：
Hsieh, Patrick C. H.
中科院分区：
文献类型：
--
作者：
Huang, Ching Ying;Nicholson, Martin W.;Hsieh, Patrick C. H.
在本研究中，我们建立了一个基于人群的人类诱导多能干细胞（hiPSC）药物筛选平台，用于毒性评估。在招募 1,000 名健康捐献者并筛选高频人类白细胞抗原 (HLA) 单倍型后，我们确定了 13 个 HLA 纯合“超级捐献者”来代表该人群。这些“超级捐助者”预计也将代表全球人口的至少 477,611,135 人。通过将这些代表性 hiPSC 分化为心肌细胞和神经元，我们展示了它们在高通量毒性筛选中的实用性。为了验证命中化合物，我们证明了命中化合物的剂量依赖性毒性并评估功能调节。我们还使用具有选定命中化合物的小鼠模型展示了可重复的体内药物毒性结果。本研究展示了使用基于人群的 hiPSC 药物筛选平台评估细胞毒性的可行性，该平台可作为研究药物发现应用中药物毒性和药物不良反应的人群间差异的创新工具。
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.