Multiplexed high-content assay for toxicity profiling using live iPSC-derived cardiomyocyte lines with lineage-specific barcoding

项目总结/摘要 人类诱导多能干细胞（hiPSC）有望改变毒理学评估，但新的 需要使其功能和结构分析的方法来提高基于hiPSC的 用于预测和机制毒理学筛选的模型。我们的项目的具体内容满足了这一需求。 目的包括：（1）开发用于产生hiPSC衍生报告细胞的新平台;（2） 产生一组具有稳定的谱系特异性的HiPSC衍生的心肌细胞（hiPSC-CM）， 荧光报告;和（3）实施和验证一个试点机器学习支持的预测 使用这些工具进行心脏毒性筛查。建议的工具配置为可扩展到其他毒理学- 相关途径和表型，使其处于独特的地位，以利用不断增长的商业需求 用于高通量预测毒理学分析。项目成果通过改善 能够快速识别特定心肌细胞谱系类型的责任，从而减少时间和成本， 精确的药物和环境化学品的心脏毒性。

Project Summary/Abstract Human induced pluripotent stem cells (hiPSCs) are poised to transform toxicological evaluation, however new approaches to enable their functional and structural profiling are needed to improve the utility of hiPSC -based models for predictive and mechanistic toxicology screening. This need is addressed by our project’s Specific Aims that encompass (1) development of a novel platform for generation of hiPSC-derived reporter cells; (2) generation of a panel of multicolor hiPSC-derived cardiomyocytes (hiPSC-CMs) with stable lineage specific fluorescent reporters; and (3) implementation and validation of a pilot machine learning-enabled predictive cardiotoxicity screen using these tools. The proposed tools are configured to be extensible to other toxicology- relevant pathways and phenotypes making it uniquely positioned to capitalize on the growing commercial need for high-throughput predictive toxicology assays. The project deliverables benefit public health by improving the ability to rapidly identify liabilities in specific cardiomyocyte lineage types, thus reducing the time and cost to pinpoint cardiotoxicity of pharmaceutical and environmental chemicals.