title: Activin A-Smad Signaling Mediates Connective Tissue Growth Factor Synthesis in Liver Progenitor Cells.
abstract: Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in LPCs remains elusive. In this study, we report that Activin A is an inducer of CTGF/CCN2 in LPCs. Here we show that expression of both Activin A and CTGF/CCN2 were upregulated in the cirrhotic liver, and the expression of Activin A positively correlates with that of CTGF/CCN2 in liver tissues. We go on to show that Activin A induced de novo synthesis of CTGF/CCN2 in LPC cell lines LE/6 and WB-F344. Furthermore, Activin A contributed to autonomous production of CTGF/CCN2 in liver progenitor cells (LPCs) via activation of the Smad signaling pathway. Smad2, 3 and 4 were all required for this induction. Collectively, these results provide evidence for the fibrotic role of LPCs in the liver and suggest that the Activin A-Smad-CTGF/CCN2 signaling in LPCs may be a therapeutic target of liver fibrosis.
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. dingzeyang@hust.edu.cn.
authors.forename: Ze-Yang
authors.initials: ZY
authors.lastname: Ding
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. jgnlh@163.com.|Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. jgnlh@163.com.
authors.forename: Guan-Nan
authors.initials: GN
authors.lastname: Jin
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. freeskywang@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. sunyimin224@163.com.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Sun
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. chenweixunclark@163.com.
authors.forename: Wei-Xun
authors.initials: WX
authors.lastname: Chen
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. chenlin_tj@126.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. lianghuifang1997@126.com.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Liang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. dattapk@uab.edu.
authors.forename: Pran K
authors.initials: PK
authors.lastname: Datta
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA. ming-zhi.zhang@vanderbilt.edu.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. bixiangzhang@tjh.tjmu.edu.cn.
authors.forename: Bixiang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. xpchen@tjh.tjmu.edu.cn.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism*; D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C526317:CCN2 protein, human; D051785:Smad Proteins; C422405:activin A; D028341:Activins; D055513:Connective Tissue Growth Factor
keywords: Activin A; Smad proteins; connective tissue growth factor; liver fibrosis; oval cell