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RNA-sequencing with human liver organoids derived from human induced pluripotent stem cells

ABSTRACT: We established a human liver organoid (HLO) based screening model for analyzing DILI pathology at organoid resolution. HLO contains polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNAseq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. By developing a 384 well based high-speed live imaging platform, we successfully developed a Liver organoid-based Toxicity screen (LoT) with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity. We functionally validated LoT with 238 marketed drugs at 4 different concentrations. LoT positively predicts genomic predisposition (CYP2C9*2) for Bosentan-induced cholestasis. Thus, LoT is a high-fidelity model for drug safety with a cost-effective platform, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141183 | GEO | 2020/10/18

REPOSITORIES: GEO

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