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Cited by 167Liver physiology and pathologyPluripotent Stem Cells ResearchMesenchymal stem cell research

Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens

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Fu, Gong-Bo, Huang, Wei-Jian, Zeng, Min, Zhou, Xu, Wu, Hong-Ping, Liu, Chang-Cheng, Wu, Han, Weng, Jun +12 more·2019·Cell Research
DOI 10.1038/s41422-018-0103-xPMC PMC6318298
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Abstract

The study of pathophysiological mechanisms in human liver disease has been constrained by the inability to expand primary hepatocytes in vitro while maintaining proliferative capacity and metabolic function. We and others have previously shown that mouse mature hepatocytes can be converted to liver progenitor-like cells in vitro with defined chemical factors. Here we describe a protocol achieving efficient conversion of human primary hepatocytes into liver progenitor-like cells (HepLPCs) through delivery of developmentally relevant cues, including NAD + -dependent deacetylase SIRT1 signaling. These HepLPCs could be expanded significantly during in vitro passage. The expanded cells can readily be converted back into metabolically functional hepatocytes in vitro and upon transplantation in vivo. Under three-dimensional culture conditions, differentiated cells generated from HepLPCs regained the ability to support infection or reactivation of hepatitis B virus (HBV). Our work demonstrates the utility of the conversion between hepatocyte and liver progenitor-like cells for studying HBV biology and antiviral therapies. These findings will facilitate the study of liver diseases and regenerative medicine.

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  • Wnt/β-catenin stimulation together with conventional mitogens such as HGF and EGF initiates a regeneration-like phase in which quiescent hepatocytes re-enter the cell cycle and expand while maintaining the ability to regain a mature hepatocyte phenotype upon cessation of mitogenic stimuli.

    “These signals initiate a regeneration-like phase: quiescent hepatocytes re-enter the cell cycle and experience significant expansion while maintaining the ability to regain a mature hepatocyte phenotype upon the cessation of mitogenic stimuli [10].”

    From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [10]

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  • SIRT1 activity is essential for transformation of primary hepatocytes into proliferative progenitor-like cells; inhibition of SIRT1 results in growth cessation and triggers apoptosis.

    “The activity of SIRT1 is essential for the transformation of PHs into proliferative progenitor-like cells; the inhibition of SIRT1 results in growth cessation and triggers apoptosis [10].”

    From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [10]

  • Defined chemical and growth factor-based protocols can temporarily induce hepatocytes into a proliferative, progenitor-like state, followed by a maturation phase that restores differentiated hepatic functions.

    “First, defined chemical and growth factor-based protocols can temporarily induce hepatocytes into a proliferative, progenitor-like state, followed by a maturation phase that restores differentiated hepatic functions.”

    From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [10]

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Research works printed but not linked: 27

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Authors
Fu, G.-B., Huang, W.-J., Zeng, M., Zhou, X., Wu, H.-P., Liu, C.-C., Wu, H., Weng, J., Zhang, H.-D., Cai, Y.-C., Ashton, C., Ding, M., Tang, D., Zhang, B.-H., Gao, Y., Yu, W.-F., Zhai, B., He, Z.-Y., Wang, H.-Y., & Yan, H.-X.
Affiliations
  • Second Military Medical University (CN)
  • Zhujiang Hospital (CN)
  • University of Southern California (US)
  • Shanghai Jiao Tong University (CN)
Corresponding author
  • Zhai, Bo
  • Yan, He-Xin
ORCID
Venue
Cell Research
Publisher
Springer Science and Business Media LLC
Published
2018-10-25
Volume
29
Issue
1
Pages
8-22
ISSN
  • 1001-0602 (ISSN-L)
  • 1748-7838
DOI
10.1038/s41422-018-0103-x
PMC
PMC6318298
OpenAlex
W2898572616
Cited by
167
References
4
Citations by year
2026: 12 · 2025: 17 · 2024: 19 · 2023: 23 · 2022: 23 · 2021: 33 · 2020: 27 · 2019: 13
FWCI
11.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Chinese Ministry of Science and Technology | Department of S and T for Social Development (2018YFA0108200, 2016YFC1101402)
  • National Natural Science Foundation of China (31571477)
  • Science and Technology Commission of Shanghai Municipality (16XD1403300, 17431906600)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
primary human hepatocytes, SIRT1, NAD+-dependent deacetylase, hepatocyte expansion, hepatocyte differentiation, hepatitis B virus, HBV reactivation, 3D cell culture, liver regeneration, antiviral therapy
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Hepatitis B, Hepatitis B virus, Humans, Liver, Stem Cells, Hepatocytes, Mice, Sirtuin 1

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