RT Journal Article
SR Electronic
T1 HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 2044
OP 2056
DO 10.1136/gutjnl-2018-316091
VO 68
IS 11
A1 Lunzhi Yuan
A1 Jing Jiang
A1 Xuan Liu
A1 Yali Zhang
A1 Liang Zhang
A1 Jiaojiao Xin
A1 Kun Wu
A1 Xiaoling Li
A1 Jiali Cao
A1 Xueran Guo
A1 Dongyan Shi
A1 ­Jun Li­
A1 Longyan Jiang
A1 Suwan Sun
A1 Tengyun Wang
A1 Wangheng Hou
A1 Tianying Zhang
A1 Hua Zhu
A1 Jun Zhang
A1 Quan Yuan
A1 Tong Cheng
A1 Jun Li
A1 Ningshao Xia
YR 2019
UL http://gut.bmj.com/content/68/11/2044.abstract
AB 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.