title: Deactivation of hepatic stellate cells during liver fibrosis resolution in mice.
abstract: OBJECTIVE
  Activated hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, undergo apoptosis after cessation of liver injury, which contributes to resolution of fibrosis. In this study, we investigated whether HSC deactivation constitutes an additional mechanism of liver fibrosis resolution.
  
  
  METHODS
  HSC activation and deactivation were investigated by single-cell PCR and genetic tracking in transgenic mice that expressed a tamoxifen-inducible CreER under control of the endogenous vimentin promoter (Vimentin-CreER).
  
  
  RESULTS
  Single-cell quantitative polymerase chain reaction demonstrated activation of almost the entire HSC population in fibrotic livers, and a gradual decrease of HSC activation during fibrosis resolution, indicating deactivation of HSCs. Vimentin-CreER marked activated HSCs, demonstrated by a 6- to 16-fold induction of a membrane-bound green fluorescent protein (mGFP) Cre-reporter after injection of carbon tetrachloride, in liver and isolated HSCs, and a shift in localization of mGFP-marked HSCs from peri-sinusoidal to fibrotic septa. Tracking of mGFP-positive HSCs revealed the persistence of 40%-45% of mGFP expression in livers and isolated HSCs 30-45 days after carbon tetrachloride was no longer administered, despite normalization of fibrogenesis parameters; these findings confirm reversal of HSC activation. After fibrosis resolution, mGFP expression was observed again in desmin-positive peri-sinusoidal HSCs; no mGFP expression was detected in hepatocytes or cholangiocytes, excluding mesenchymal-epithelial transition. Notably, reverted HSCs remained in a primed state, with higher levels of responsiveness to fibrogenic stimuli.
  
  
  CONCLUSIONS
  In mice, reversal of HSC activation contributes to termination of fibrogenesis during fibrosis resolution, but results in higher responsiveness of reverted HSCs to recurring fibrogenic stimulation.
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
authors: Juliane S
authors: JS
authors: Troeger
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
authors: Ingmar
authors: I
authors: Mederacke
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
authors: Geum-Youn
authors: GY
authors: Gwak
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.|Institute of Human Nutrition, Columbia University, New York, NY.
authors: Dianne H
authors: DH
authors: Dapito
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
authors: Xueru
authors: X
authors: Mu
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
authors: Christine C
authors: CC
authors: Hsu
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.
authors: Jean-Philippe
authors: JP
authors: Pradere
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.|Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.
authors: Richard A
authors: RA
authors: Friedman
authors: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY.|Institute of Human Nutrition, Columbia University, New York, NY.
authors: Robert F
authors: RF
authors: Schwabe
mesh_terms: D000199:Actins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D015870:Gene Expression; D005821:Genetic Techniques; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D019426:Integrases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014746:Vimentin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014746:Vimentin; C544013:alpha-smooth muscle actin, mouse; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; D002251:Carbon Tetrachloride; C045073:Cre recombinase; D019426:Integrases