单位：[1]Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China华中科技大学同济医学院附属同济医院肝脏外科[2]Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China华中科技大学同济医学院附属协和医院[3]Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA[4]Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA[5]Authors to whom correspondence should be addressed.
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.View Full-Text
基金：
National Nature Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81401997, 81402410, 81372327, 81500565]; State Key Project on Infection Disease of China [2016ZX10002018-016]; Chinese Ministry of Public Health for Key Clinical Project [[2010] 493-51]; Major Science Foundation of the Ministry of Health of China [201302009]
