title: Analysis of epithelial-mesenchymal transition markers in the histogenesis of hepatic progenitor cell in HBV-related liver diseases.
abstract: BACKGROUND
  The origin and heterogeneity of hepatic progenitor cells (HPCs) remain unclear. This study aimed to investigate the involvement of epithelial-mesenchymal transition (EMT) in the histogenesis of HPCs.
  
  
  METHODS
  Surgical liver specimens from patients with HBV-related hepatitis and cirrhosis were investigated with double immunofluorescence labeling to detect antigens associated with HPCs and EMT. Ductular reactions were subjected to quantitative reverse transcription PCR following isolation by laser capture microdissection. Electron microscopic examination was performed to find an ultrastructural evidence of EMT.
  
  
  RESULTS
  The number of EpCAM-positive HPCs was proportional to the disease severity. The S100A4 expression of HPCs was firstly observed in mild hepatitis and increased significantly in moderate hepatitis, but decreased in severe hepatitis and cirrhosis. The levels of MMP-2, Twist, and Snail increased in direct proportion to the number of HPCs. Some hepatocytes adjacent to portal tracts in cirrhosis showed positivity for MMP-2. Although CK7 and E-cadherin levels decreased in mild and moderate hepatitis, HPCs re-expressed both of them in severe hepatitis and cirrhosis. However, HPCs expressed neither vimentin nor αSMA. The relative mRNA expression levels of EpCAM and EMT-associated markers supported immunohistochemical results. Electron microscopic examination demonstrated the existence of intercellular junctions among HPCs, cholangiocytes, and intermediate hepatocyte-like cells.
  
  
  CONCLUSIONS
  We provided preliminary evidence for the involvement of EMT in the histogenesis of HPCs from cholangiocytes in HBV-related liver diseases. HPCs may re-transdifferentiate into hepatocytes, and the differentiation direction depends, at least in part, on interactions between HPCs and the surrounding microenvironment, especially the non-resolving inflammation caused by HBV infection.
authors.affiliation: Department of General Surgery, Jiangxi Children's Hospital, Nanchang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.|Department of Gastroenterology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Nong-Rong
authors.initials: NR
authors.lastname: Wang
authors.affiliation: Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Hua-Feng
authors.initials: HF
authors.lastname: Wang
authors.affiliation: Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.|Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Emergency Department, The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Deng
authors.affiliation: Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Gong
authors.affiliation: Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Lou
authors.affiliation: Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Yu
authors.affiliation: Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Lv
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Hu
authors.affiliation: Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Qi
authors.affiliation: Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Yan-Juan
authors.initials: YJ
authors.lastname: Deng
authors.affiliation: Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Gong
authors.affiliation: Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Wang
authors.affiliation: Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.|Department of Pathology, Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Jia-Cheng
authors.initials: JC
authors.lastname: Xiao
authors.affiliation: Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China. beandeng@ncu.edu.cn.|Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, China. beandeng@ncu.edu.cn.|Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China. beandeng@ncu.edu.cn.|Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, 133 South Guangchang Road, Nanchang, 330006, Jiangxi, China. beandeng@ncu.edu.cn.
authors.forename: Huan
authors.identifier: http://orcid.org/0000-0002-1596-2013
authors.initials: H
authors.lastname: Deng
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005455:Fluorescent Antibody Technique; D006509:Hepatitis B / Q000473:pathology*; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D061346:Laser Capture Microdissection; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D013234:Stem Cells / Q000166:cytology*
chemical_list: D015415:Biomarkers
keywords: Cholangiocyte; Epithelial-mesenchymal transition; HBV; Hepatic progenitor cell; Histogenesis