Generation of endoderm- and mesoderm-derived quiescent hepatic stellate cells (qHSCs)
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Induced qHSC-like cells can be activated into myofibroblasts in vitro
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Induced qHSC-like cells can respond to hepatoxicity from thioacetamide treatment
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Hepatitis B and C virus infection can convert qHSC-like cells into activated HSCs
Summary
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.
Graphical abstract
Keywords
human embryonic stem cells
induced hepatic stellate cells
model
fibrogenesis
hepatoxicity
liver fibrosis
viral hepatitis
Data and code availability
The transcriptomic data generated during this study are available at NCBI (SRA: PRJNA727427)