肝硬化
免疫学
间充质干细胞
免疫系统
医学
干细胞
乙型肝炎病毒
肝炎
移植
生物
内科学
病理
病毒
遗传学
作者
Lunzhi Yuan,Jing Jiang,Xuan Li,Yali Zhang,Liang Zhang,Jiaojiao Xin,Kaisheng Wu,Xiaoling Li,Jiali Cao,Xue-Ran Guo,Dongyan Shi,Jun Li,Liangliang Jiang,Suwan Sun,Tengyun Wang,Wangheng Hou,Tianying Zhang,Hua Zhu,Jun Zhang,Quan Yuan,Tong Cheng,Ningshao Xia
出处
期刊:Gut
[BMJ]
日期:2019-01-30
卷期号:68 (11): 2044-2056
被引量:41
标识
DOI:10.1136/gutjnl-2018-316091
摘要
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).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.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.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.
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