Stem Cell Reports
Volume 17, Issue 11, 8 November 2022, Pages 2531-2547
Journal home page for Stem Cell Reports

Article
Generation of functionally competent hepatic stellate cells from human stem cells to model liver fibrosis in vitro

https://doi.org/10.1016/j.stemcr.2022.09.010Get rights and content
Under a Creative Commons license
open access

Highlights

  • Generation of endoderm- and mesoderm-derived quiescent hepatic stellate cells (qHSCs)

  • Induced qHSC-like cells can be activated into myofibroblasts in vitro

  • Induced qHSC-like cells can respond to hepatoxicity from thioacetamide treatment

  • 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.

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)

Cited by (0)

6

These authors contributed equally