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...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.展开更多
基金supported by grants from Shanghai Science and Technology Commission(21140901700,20dz1101400)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030402)+2 种基金the National Natural Science Foundation of China(31971063,82070824)China Postdoctoral Science Foundation(2019M661661)Youth Innovation Promotion Association of CAS(2022274).
文摘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.
