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Original article
HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation
  1. Lunzhi Yuan1,
  2. Jing Jiang2,
  3. Xuan Liu1,
  4. Yali Zhang1,
  5. Liang Zhang1,
  6. Jiaojiao Xin2,
  7. Kun Wu1,
  8. Xiaoling Li1,
  9. Jiali Cao1,
  10. Xueran Guo1,
  11. Dongyan Shi2,
  12. ­Jun Li­3,
  13. Longyan Jiang2,
  14. Suwan Sun2,
  15. Tengyun Wang1,
  16. Wangheng Hou1,
  17. Tianying Zhang1,
  18. Hua Zhu4,
  19. Jun Zhang1,
  20. Quan Yuan1,
  21. Tong Cheng1,
  22. Jun Li2,
  23. Ningshao Xia1
  1. 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. 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. 3 Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  4. 4 Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
  1. Correspondence to Associate Professor Tong Cheng, 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, 361102, China; tcheng{at}xmu.edu.cn, Professor Jun Li, 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 310003, China; lijun2009{at}zju.edu.cn and Professor Ningshao Xia, 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, 361102, China; nsxia{at}xmu.edu.cn

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.

  • hepatitis B
  • chronic hepatitis
  • liver cirrhosis
  • stem cells

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Footnotes

  • LY, JJ and XL contributed equally.

  • Contributors LY, JJ and XL contributed equally to this work. LY, JJ, XL, LZ, JJ, DS, YZ and SS established the cell culture system and performed the measurements of hBMSCs. LY, LX, LZ, YZ, TW and KW generated the animal model. LY, XL, JC and XG performed the HBV infection studies. LY, JJ, XL, LZ and JL (the 12th author) performed the histological analyses of chronic hepatitis and liver cirrhosis. WH, TZ, HZ, JZ and QY participated in the experimental design and data analyses. JL (the 22th author), LZ, JJ and XL wrote the manuscript. TC, JL (the 22th author) and NX supervised the project.

  • Funding This work was supported by the National Science and Technology Major Project (grant nos. 2017ZX10304402, 2017ZX10203201 and 2018ZX09711003-005-003), the National Natural Science Foundation of China(grant nos. 81672023, 81571818 and 81771996), the Scientific Research Foundation of the State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics (grant no 2016ZY005), Zhejiang Province and State’s Key Project of the Research and Development Plan of China (grant nos 2017C01026 and 2016YFC1101304/3).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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