Modeling drug-induced liver injury and screening for anti-hepatofibrotic compounds using human PSC-derived organoids

Preclinical models that can accurately predict the toxicity and efficacy of candidate drugs to human liver tissue are in urgent need. Human liver organoid (HLO) derived from human pluripotent stem cells offers a possible solution. Herein, we generated HLOs, and demonstrated the utility of these HLOs in modeling a diversity of phenotypes associated with drug-induced liver injury (DILI), including steatosis, fibrosis, and immune responses. Phenotypic changes in HLOs after treatment with tool compounds such as acetaminophen, fialuridine, methotrexate, or TAK-875 showed high concordance with human clinical data in drug safety testings. Moreover, HLOs were able to model liver fibrogenesis induced by TGFβ or LPS treatment. We further devised a high-content analysis system, and established a high-throughput anti-fibrosis drug screening system using HLOs. SD208 and Imatinib were identified that can significantly suppress fibrogenesis induced by TGFβ, LPS, or methotrexate. Taken together, our studies demonstrated the potential applications of HLOs in drug safety testing and anti-fibrotic drug screening.

 

Comments：

This study highlights the utility of human liver organoids (HLOs) derived from human pluripotent stem cells in modeling drug-induced liver injury (DILI) and liver fibrosis. The authors showed that HLOs can accurately predict the toxicity and efficacy of candidate drugs to human liver tissue. Treatment with tool compounds such as acetaminophen, fialuridine, methotrexate, or TAK-875 induced phenotypic changes in HLOs that showed high concordance with human clinical data in drug safety testing.

In addition, HLOs were able to model liver fibrogenesis induced by TGFβ or LPS treatment. The authors devised a high-content analysis system and established a high-throughput anti-fibrosis drug screening system using HLOs. They identified SD208 and Imatinib as potential anti-fibrotic drugs that can significantly suppress fibrogenesis induced by TGFβ, LPS, or methotrexate.

Overall, the findings of this study suggest that HLOs have the potential to serve as a preclinical model for drug safety testing and anti-fibrotic drug screening. This could help to reduce the need for animal testing and improve the efficiency of drug development. However, further studies are needed to validate the utility of HLOs in predicting drug toxicity and efficacy in humans.

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GPR