title: Early activated hepatic stellate cell-derived molecules reverse acute hepatic injury.
abstract: OBJECTIVE
  To test whether hepatic stellate cells (HSCs) at different activation stages play different roles in acetaminophen (APAP)-induced acute liver injury (ALI).
  
  
  METHODS
  HSCs were isolated from mouse liver and cultured in vitro. Morphological changes of initiation HSCs [HSCs (5d)] and perpetuation HSCs [HSCs (p3)] were observed by immunofluorescence and transmission electron microscopy. The protective effects of HSC-derived molecules, cell lysates and HSC-conditioned medium (HSC-CM) were tested in vivo by survival and histopathological analyses. Liver injury was determined by measuring aminotransferase levels in the serum and by histologic examination of tissue sections under a light microscope. Additionally, to determine the molecular mediators of the observed protective effects of initiation HSCs, we examined HSC-CM using a high-density protein array.
  
  
  RESULTS
  HSCs (5d) and HSCs (p3) had different morphological and phenotypic traits. HSCs (5d) presented a star-shaped appearance with expressing α-SMA at non-uniform levels between cells. However, HSCs (p3) evolved into myofibroblast-like cells without lipid droplets and expressed a uniform and higher level of α-SMA. HSC-CM (5d), but not HSC-CM (p3), provided a significant survival benefit and showed a dramatic reduction of hepatocellular necrosis and panlobular leukocyte infiltrates in mice exposed to APAP. However, this protective effect was abrogated at higher cell masses, indicating a therapeutic window of effectiveness. Furthermore, the protein array screen revealed that HSC-CM (5d) was composed of many chemokines and growth factors that correlated with inflammatory inhibition and therapeutic activity. When compared with HSC-CM (p3), higher levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-1γ, hepatocyte growth factor, interleukin-10, and matrix metalloproteinase-2, but lower levels of stem cell factor and Fas-Ligand were observed in HSC-CM (5d).
  
  
  CONCLUSIONS
  These data indicated that initiation HSCs and perpetuation HSCs were different in morphology and protein expression, and provided the first experimental evidence of the potential medical value of initiation HSC-derived molecules in the treatment of ALI.
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Wen-Ju
authors.initials: WJ
authors.lastname: Chang
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Lu-Jun
authors.initials: LJ
authors.lastname: Song
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Tuo
authors.initials: T
authors.lastname: Yi
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Kun-Tang
authors.initials: KT
authors.lastname: Shen
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Hong-Shan
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Gao
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Xu
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Wei-Xin
authors.initials: WX
authors.lastname: Niu
authors.affiliation: Wen-Ju Chang, Lu-Jun Song, Tuo Yi, Kun-Tang Shen, Hong-Shan Wang, Xiao-Dong Gao, Min Li, Jian-Min Xu, Wei-Xin Niu, Xin-Yu Qin, Department of General Surgery, Zhongshan Hospital, Institute of General Surgery, Fudan University, Shanghai 200032, China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Qin
mesh_terms: D000082:Acetaminophen; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D048430:Cell Shape; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018925:Chemokines / Q000008:administration & dosage / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D009336:Necrosis; D019899:Paracrine Communication; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D018925:Chemokines; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D000082:Acetaminophen
keywords: Acute liver injury; Hepatic stellate cells; Initiation and perpetuation