title: Early activated hepatic stellate cell-derived paracrine molecules modulate acute liver injury and regeneration.
abstract: The effects of paracrine action from early activated hepatic stellate cells (HSCs) on resident liver epithelium cells are not clear. Here, we investigated whether a systemic infusion of early activated HSC-derived paracrine factors (HSC-CM) would evoke an enhanced liver protective response in acetaminophen (APAP)-induced acute liver injury (ALI) in mice and explored the possible underlying mechanisms. The survival rate, liver injury, and liver regeneration were analyzed in mice with or without HSC-CM treatment in vivo. A systemic infusion of HSC-CM provided a significant survival benefit in APAP-induced ALI. HSC-CM therapy resulted in a reduction of hepatocellular death and increased numbers of both proliferating hepatocytes and adult hepatic progenitor cells (AHPCs) with up-regulation of liver regeneration relevant genes. The HSC-CM treatment reduced leukocyte infiltration and down-regulated systemic inflammation with decreases in IFN-γ, IL-1ra, IL-1β, TNF-α, and increases in IL-10. The direct anti-death and pro-regeneration effects of HSC-CM on AHPCs were demonstrated using in vitro assays. Treatment with HSC-CM promoted AHPCs proliferation and resulted in increased pAkt expression in vitro, and this effect was abolished by the PI3K/Akt inhibitor LY294002. These data provide evidence that early activated HSC-CM therapy offered trophic support to the acutely injured liver by inhibiting liver cell death and stimulating regeneration, potentially creating a new method for the treatment of ALI.
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Wenju
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Lujun
authors.initials: L
authors.lastname: Song
authors.affiliation: Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.|Treatment and Research Center for Liver Cancer Department, 302 Military Hospital of China, Beijing, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Chang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai, China.
authors.forename: Weixin
authors.initials: W
authors.lastname: Niu
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002867:Chromones / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D000082:Acetaminophen; D002867:Chromones; D017077:Culture Media, Conditioned; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one