Generation of functionally competent hepatic stellate cells from human stem cells to model liver fibrosis in vitro
Xinyuan Lai, Chuanyun Li, Chengang Xiang, Zihang Pan, Kai Zhang, Lei Wang, Bingqing Xie, Junning Cao, Jihang Shi, Juan Deng, Shichun Lu, Hongkui Deng, Hui Zhuang, Tong Li, Yan Shi, Kuanhui Xiang
Abstract
The detailed understanding of fibrogenesis has been hampered by a lack of important functional quiescence characteristics and an in vitro model to recapitulate hepatic stellate cell (HSC) activation. In our study, we establish robust endoderm- and mesoderm-sourced quiescent-like induced HSCs (iHSCs) derived from human pluripotent stem cells. Notably, iHSCs present features of mature HSCs, including accumulation of vitamin A in the lipid droplets and maintained quiescent features. In addition, iHSCs display a fibrogenic response and secrete collagen I in response to hepatoxicity caused by thioacetamide, acetaminophen, and hepatitis B and C virus infection. Antiviral therapy attenuated virally induced iHSC activation. Interestingly, endoderm- and mesoderm-derived iHSCs showed similar iHSC phenotypes. Therefore, we provide a novel and robust method to efficiently generate functional iHSCs from hESC and iPSC differentiation, which could be used as a model for hepatocyte toxicity prediction, anti-liver-fibrosis drug screening, and viral hepatitis-induced liver fibrosis.