title: Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology.
abstract: Although organ fibrosis causes significant morbidity and mortality in chronic diseases, the lack of detailed knowledge about specific cellular contributors mediating fibrogenesis hampers the design of effective antifibrotic therapies. Different cellular sources, including tissue-resident and bone marrow-derived fibroblasts, pericytes and epithelial cells, have been suggested to give rise to myofibroblasts, but their relative contributions remain controversial, with profound differences between organs and different diseases. Here we employ a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells (HSCs), a liver-specific pericyte population, to demonstrate that HSCs give rise to 82-96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease. Moreover, we exclude that HSCs function as facultative epithelial progenitor cells in the injured liver. On the basis these findings, HSCs should be considered the primary cellular target for antifibrotic therapies across all types of liver disease.
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Mederacke
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Troeger
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Huebener
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Xueru
authors.initials: X
authors.lastname: Mu
authors.affiliation: Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
authors.forename: Dianne H
authors.initials: DH
authors.lastname: Dapito
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pradere
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.|Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
mesh_terms: D000818:Animals; D005260:Female; D017930:Genes, Reporter; D055166:Hepatic Stellate Cells / Q000473:pathology / Q000502:physiology*; D019426:Integrases / Q000235:genetics; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D058628:Myofibroblasts / Q000473:pathology / Q000502:physiology*
chemical_list: C045073:Cre recombinase; D019426:Integrases