title: Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis.
abstract: Myofibroblasts produce the fibrous scar in hepatic fibrosis. In the carbon tetrachloride (CCl(4)) model of liver fibrosis, quiescent hepatic stellate cells (HSC) are activated to become myofibroblasts. When the underlying etiological agent is removed, clinical and experimental fibrosis undergoes a remarkable regression with complete disappearance of these myofibroblasts. Although some myofibroblasts apoptose, it is unknown whether other myofibroblasts may revert to an inactive phenotype during regression of fibrosis. We elucidated the fate of HSCs/myofibroblasts during recovery from CCl(4)- and alcohol-induced liver fibrosis using Cre-LoxP-based genetic labeling of myofibroblasts. Here we demonstrate that half of the myofibroblasts escape apoptosis during regression of liver fibrosis, down-regulate fibrogenic genes, and acquire a phenotype similar to, but distinct from, quiescent HSCs in their ability to more rapidly reactivate into myofibroblasts in response to fibrogenic stimuli and strongly contribute to liver fibrosis. Inactivation of HSCs was associated with up-regulation of the anti-apoptotic genes Hspa1a/b, which participate in the survival of HSCs in culture and in vivo.
authors.affiliation: Department of Medicine, School of Pharmacy, University of California, San Diego, CA 92093, USA. tkisseleva@ucsd.edu
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kisseleva
authors.forename: Min
authors.initials: M
authors.lastname: Cong
authors.forename: Yonghan
authors.initials: Y
authors.lastname: Paik
authors.forename: David
authors.initials: D
authors.lastname: Scholten
authors.forename: Chunyan
authors.initials: C
authors.lastname: Jiang
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.forename: Thomas
authors.initials: T
authors.lastname: Moore-Morris
authors.forename: Brian
authors.initials: B
authors.lastname: Scott
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dillmann
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D013629:Tamoxifen