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

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...

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Bibliographic Details
Published in:Cell research 2019-01, Vol.29 (1), p.8-22
Main Authors: Fu, Gong-Bo, Huang, Wei-Jian, Zeng, Min, Zhou, Xu, Wu, Hong-Ping, Liu, Chang-Cheng, Wu, Han, Weng, Jun, Zhang, Hong-Dan, Cai, Yong-Chao, Ashton, Charles, Ding, Min, Tang, Dan, Zhang, Bao-Hua, Gao, Yi, Yu, Wei-Feng, Zhai, Bo, He, Zhi-Ying, Wang, Hong-Yang, Yan, He-Xin
Format: Article
Language:English
Subjects:
13/1
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13/89
14/63
38
38/91
631/532/2435
631/532/489
Activation
Animals
Antiviral agents
Biomedical and Life Sciences
Cell Biology
Cell culture
Cell Differentiation
Cells, Cultured
Conversion
Hepatitis B
Hepatitis B - pathology
Hepatitis B virus - physiology
Hepatocytes
Hepatocytes - metabolism
Hepatocytes - pathology
Humans
Life Sciences
Liver
Liver - pathology
Liver diseases
Mice
NAD
Organic chemistry
Regenerative medicine
SIRT1 protein
Sirtuin 1 - metabolism
Stem Cells - cytology
Stem Cells - pathology
Transplantation
Viruses
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Summary: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.
ISSN:1001-0602
1748-7838
DOI:10.1038/s41422-018-0103-x