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Hepatitis B and Hepatitis C Virus Infection Promote Liver Fibrogenesis through a TGF-β1-Induced OCT4/Nanog Pathway.

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机构： [1]Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China [2]Department of Infectious Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China [3]Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA [4]Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan Province, China [5]Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China [6]Southwest University, College of Animal Science and Technology, Chongqing, China [7]Department of Microbiology, College of Basic Medical Science, Chongqing Medical University, Chongqing, China [8]Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China [9]Department of Hepatology, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu Province, China [10]Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC [11]Department of Gastroenterology, St Vincent’s Hospital, Fitzroy, Victoria, Australia

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Hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection accelerates liver fibrosis progression compared with HBV or HCV monoinfection. Octamer binding transcription factor 4 (OCT4) and Nanog are direct targets of the profibrogenic TGF-β1 signaling cascade. We leveraged a coculture model to monitor the effects of HBV and HCV coinfection on fibrogenesis in both sodium taurocholate cotransporting polypeptide-transfected Huh7.5.1 hepatoma cells and LX2 hepatic stellate cells (HSCs). We used CRISPR-Cas9 to knock out OCT4 and Nanog to evaluate their effects on HBV-, HCV-, or TGF-β1-induced liver fibrogenesis. HBV/HCV coinfection and HBx, HBV preS2, HCV Core, and HCV NS2/3 overexpression increased TGF-β1 mRNA levels in sodium taurocholate cotransporting polypeptide-Huh7.5.1 cells compared with controls. HBV/HCV coinfection further enhanced profibrogenic gene expression relative to HBV or HCV monoinfection. Coculture of HBV and HCV monoinfected or HBV/HCV coinfected hepatocytes with LX2 cells significantly increased profibrotic gene expression and LX2 cell invasion and migration. OCT4 and Nanog guide RNA independently suppressed HBV-, HCV-, HBV/HCV-, and TGF-β1-induced α-SMA, TIMP-1, and Col1A1 expression and reduced Huh7.5.1, LX2, primary hepatocyte, and primary human HSC migratory capacity. OCT4/Nanog protein expression also correlated positively with fibrosis stage in liver biopsies from patients with chronic HBV or HCV infection. In conclusion, HBV and HCV independently and cooperatively promote liver fibrogenesis through a TGF-β1-induced OCT4/Nanog-dependent pathway.Copyright © 2022 by The American Association of Immunologists, Inc.

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大类 | 2 区

医学

小类 | 3 区免疫学

最新[2023]版：

大类 | 3 区医学

小类 | 3 区免疫学

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出版当年[2022]版：

Q2 IMMUNOLOGY

最新[2023]版：

Q2 IMMUNOLOGY

影响因子： 3.6 最新[2023版] 4.2 最新五年平均 4.4 出版当年[2022版] 5.2 出版当年五年平均 5.43 出版前一年[2021版] 3.6 出版后一年[2023版]

第一作者：

第一作者机构： [1]Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China [2]Department of Infectious Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China [3]Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

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通讯机构： [3]Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA [*1]Liver Center and Gastrointestinal Division, Department of Medicine,Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Warren 1007, Boston, MA 02114

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