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Gut. 2019 Jan 30. pii: gutjnl-2018-316091. doi: 10.1136/gutjnl-2018-316091. [Epub ahead of print]

HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation.

Author information

1
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences and School of Public Health, Xiamen University, Xiamen, China.
2
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
3
Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
4
Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
#
Contributed equally

Abstract

OBJECTIVE:

Developing a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to identify intervention strategies for HBV-related liver diseases. This study aimed to develop an HBV-induced chronic hepatitis and cirrhosis mouse model through transplantation of human bone marrow mesenchymal stem cells (hBMSCs).

DESIGN:

Transplantation of hBMSCs into Fah-/-Rag2-/-IL-2Rγc-/- SCID (FRGS) mice with fulminant hepatic failure (FHF) induced by hamster-anti-mouse CD95 antibody JO2 generated a liver and immune cell dual-humanised (hBMSC-FRGS) mouse. The generated hBMSC-FRGS mice were subjected to assessments of sustained viremia, specific immune and inflammatory responses and liver pathophysiological injury to characterise the progression of chronic hepatitis and cirrhosis after HBV infection.

RESULTS:

The implantation of hBMSCs rescued FHF mice, as demonstrated by robust proliferation and transdifferentiation of functional human hepatocytes and multiple immune cell lineages, including B cells, T cells, natural killer cells, dendritic cells and macrophages. After HBV infection, the hBMSC-FRGS mice developed sustained viremia and specific immune and inflammatory responses and showed progression to chronic hepatitis and liver cirrhosis at a frequency of 55% after 54 weeks.

CONCLUSION:

This new humanised mouse model recapitulates the liver cirrhosis induced by human HBV infection, thus providing research opportunities for understanding viral immune pathophysiology and testing antiviral therapies in vivo.

KEYWORDS:

chronic hepatitis; hepatitis B; liver cirrhosis; stem cells

PMID:
30700543
DOI:
10.1136/gutjnl-2018-316091
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