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

Xiaoshan Wu; Dacheng Jiang; Yi Yang; Shuang Li; Qiurong Ding

doi:10.1186/s13619-022-00148-1

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

Cell Regen. 2023 Mar 3;12(1):6. doi: 10.1186/s13619-022-00148-1.

Authors

Xiaoshan Wu^{1

2

3}, Dacheng Jiang², Yi Yang¹, Shuang Li⁴, Qiurong Ding^{5

6

7

8}

Affiliations

¹ School of Biotechnology, East China University of Science and Technology, Shanghai, 200237, P. R. China.
² CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China.
³ School of Pharmacy, Fujian Health College, Fujian, 350101, P. R. China.
⁴ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China. lishuang@sibs.ac.cn.
⁵ School of Biotechnology, East China University of Science and Technology, Shanghai, 200237, P. R. China. qrding@sibs.ac.cn.
⁶ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China. qrding@sibs.ac.cn.
⁷ Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. qrding@sibs.ac.cn.
⁸ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, P. R. China. qrding@sibs.ac.cn.

Abstract

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.

Keywords: Anti-fibrotic compounds; Drug-induced liver injury; High-content analysis; Human liver organoid; Pluripotent stem cell.

Abstract

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