title: Transforming growth factor β induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling.
abstract: Hepatic progenitor cells (HPCs) are activated in the chronic liver injury and are found to participate in the progression of liver fibrosis, while the precise role of HPCs in liver fibrosis remains largely elusive. In this study, by immunostaining of human liver sections, we confirmed that HPCs were activated in the cirrhotic liver and secreted transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF), both of which were important inducers of liver fibrosis. Besides, we used HPC cell lines LE/6 and WB-F344 as in vitro models and found that TGF-β induced secretion of CTGF in HPCs. Moreover, TGF-β signaling was intracrine activated and contributed to autonomous secretion of CTGF in HPCs. Furthermore, we found that TGF-β induced expression of CTGF was not mediated by TGF-β activated Smad signaling but mediated by TGF-β activated Erk, JNK and p38 MAPK signaling. Taken together, our results provide evidence for the role of HPCs in liver fibrosis and suggest that the production of CTGF by TGF-β activated MAPK signaling in HPCs may be a therapeutic target of liver fibrosis.
authors.affiliation: Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Ze-yang
authors.initials: ZY
authors.lastname: Ding
authors.forename: Guan-nan
authors.initials: GN
authors.lastname: Jin
authors.forename: Hui-fang
authors.initials: HF
authors.lastname: Liang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Wei-xun
authors.initials: WX
authors.lastname: Chen
authors.forename: Pran K
authors.initials: PK
authors.lastname: Datta
authors.forename: Ming-zhi
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Bixiang
authors.initials: B
authors.lastname: Zhang
authors.forename: Xiao-ping
authors.initials: XP
authors.lastname: Chen
mesh_terms: D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor
keywords: CTGF; Connective tissue growth factor; ECM; EMT; Erk; HPCs; HSCs; Hepatic progenitor cells; IFN-γ; Intracrine signaling; JNK; MAPK; PI3K; Smad-independent signaling; TGF-β; Transforming growth factor β; c-Jun N-terminal kinase; connective tissue growth factor; epithelial–mesenchymal transition; extracellular matrix; extracellular signal-regulated kinase; hepatic progenitor cells; hepatic stellate cells; interferon-γ; mitogen activated protein kinase; phosphatidylinositol 3-kinase; shRNA; small hairpin RNA; transforming growth factor β