title: Tumor necrosis factor-inducible gene 6 promotes liver regeneration in mice with acute liver injury.
abstract: BACKGROUND
  Tumor necrosis factor-inducible gene 6 protein (TSG-6), one of the cytokines released by human mesenchymal stem/stromal cells (hMSC), has an anti-inflammatory effect and alleviates several pathological conditions; however, the hepatoprotective potential of TSG-6 remains unclear. We investigated whether TSG-6 promoted liver regeneration in acute liver failure.
  
  
  METHODS
  The immortalized hMSC (B10) constitutively over-expressing TSG-6 or empty plasmid (NC: Negative Control) were established, and either TSG-6 or NC-conditioned medium (CM) was intraperitoneally injected into mice with acute liver damage caused by CCl4. Mice were sacrificed at 3 days post-CM treatment.
  
  
  RESULTS
  Higher expression and the immunosuppressive activity of TSG-6 were observed in CM from TSG-6-hMSC. The obvious histomorphological liver injury and increased level of liver enzymes were shown in CCl4-treated mice with or without NC-CM, whereas those observations were markedly ameliorated in TSG-6-CM-treated mice with CCl4. Ki67-positive hepatocytic cells were accumulated in the liver of the CCl4+TSG-6 group. RNA analysis showed the decrease in both of inflammation markers, tnfα, il-1β, cxcl1 and cxcl2, and fibrotic markers, tgf-β1, α-sma and collagen α1, in the CCl4+TSG-6 group, compared to the CCl4 or the CCl4+NC group. Protein analysis confirmed the lower expression of TGF-β1 and α-SMA in the CCl4+TSG-6 than the CCl4 or the CCl4+NC group. Immunostaining for α-SMA also revealed the accumulation of the activated hepatic stellate cells in the livers of mice in the CCl4 and CCl4+NC groups, but not in the livers of mice from the CCl4+TSG-6 group. The cultured LX2 cells, human hepatic stellate cell line, in TSG-6-CM showed the reduced expression of fibrotic markers, tgf-β1, vimentin and collagen α1, whereas the addition of the TSG-6 antibody neutralized the inhibitory effect of TSG-6 on the activation of LX2 cells. In addition, cytoplasmic lipid drops, the marker of inactivated hepatic stellate cell, were detected in TSG-6-CM-cultured LX2 cells, only. The suppressed TSG-6 activity by TSG-6 antibody attenuated the restoration process in livers of TSG-6-CM-treated mice with CCl4.
  
  
  CONCLUSIONS
  These results demonstrated that TSG-6 contributed to the liver regeneration by suppressing the activation of hepatic stellate cells in CCl4-treated mice, suggesting the therapeutic potential of TSG-6 for acute liver failure.
authors.affiliation: Department of Intergrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan, 609-735, Korea. wsh1888@nate.com.
authors.forename: Sihyung
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Life Science, Sogang University, Seoul, 121-742, Korea. jiseon80@gmail.com.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Intergrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan, 609-735, Korea. j.hyun@pusan.ac.kr.
authors.forename: Jeongeun
authors.initials: J
authors.lastname: Hyun
authors.affiliation: Department of Intergrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan, 609-735, Korea. jieun@pusan.ac.kr.
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. sukim@interchange.ubc.ca.
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.affiliation: Department of Life Science, Sogang University, Seoul, 121-742, Korea. hjcha@sogang.ac.kr.
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
authors.affiliation: Department of Intergrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan, 609-735, Korea. y.jung@pusan.ac.kr.|Department of Biological Sciences, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan, 609-735, Korea. y.jung@pusan.ac.kr.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology*; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; C513057:Tnfaip6 protein, mouse; D002251:Carbon Tetrachloride