title: Hepatic Progenitor Cells Contribute to the Progression of 2-Acetylaminofluorene/Carbon Tetrachloride-Induced Cirrhosis via the Non-Canonical Wnt Pathway.
abstract: Hepatic progenitor cells (HPCs) appear to play an important role in chronic liver injury. In this study, cirrhosis was induced in F-344 rats (n = 32) via subcutaneous injection of 50% carbon tetrachloride (CCl4) twice a week for 8 weeks. Then, 30% CCl4 was administered in conjunction with intragastric 2-acetylaminofluorine (2-AAF) for 4 weeks to induce activation of HPCs. WB-F344 cells were used to provide direct evidence for differentiation of HPCs to myofibroblasts. The results showed that after administration of 2-AAF, the hydroxyproline content and the expressions of α-SMA, Col I, Col IV, TGF-β1, CD68, TNF-α, CK19 and OV6 were significantly increased. OV6 and α-SMA were largely co-expressed in fibrous septum and the expressions of Wnt5b, frizzled2, frizzled3 and frizzled6 were markedly increased, while β-catenin expression was not statistically different among the different groups. Consistent with the above results, WB-F344 cells, treated with TGF-β1 in vitro, differentiated into myofibroblasts and α-SMA, Col I, Col IV, Wnt5b and frizzled2 expressions were significantly increased, while β-catenin expression was decreased. After blocking the non-canonical Wnt pathway via WIF-1, the Wnt5b level was down regulated, and α-SMA and F-actin expressions were significantly decreased in the WIF-1-treated cells. In conclusion, these results indicate that HPCs appear to differentiate into myofibroblasts and exhibit a profibrotic effect in progressive cirrhosis via activation of the non-canonical Wnt pathway. Blocking the non-canonical Wnt pathway can inhibit the differentiation of HPCs into myofibroblasts, suggesting that blocking this pathway and changing the fate of differentiated HPCs may be a potential treatment for cirrhosis.
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Li
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ren
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yaning
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Yuyou
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Internal Medicine, Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Zern
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Chen
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Chenghai
authors.initials: C
authors.lastname: Liu
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
mesh_terms: D015073:2-Acetylaminofluorene; D000818:Animals; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D060449:Wnt Signaling Pathway
chemical_list: D015073:2-Acetylaminofluorene; D002251:Carbon Tetrachloride