title: Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice.
abstract: The origin of fibrogenic cells in liver fibrosis remains controversial. We assessed the emerging concept that hepatocytes contribute to production of extracellular matrix (ECM) in liver fibrosis through epithelial-mesenchymal transition (EMT). We bred triple transgenic mice expressing ROSA26 stop beta-galactosidase (beta-gal), albumin Cre, and collagen alpha1(I) green fluorescent protein (GFP), in which hepatocyte-derived cells are permanently labeled by beta-gal and type I collagen-expressing cells are labeled by GFP. We induced liver fibrosis by repetitive carbon tetrachloride (CCl(4)) injections. Liver sections and isolated cells were evaluated for GFP and beta-gal as well as expression of alpha-smooth muscle actin (alpha-SMA) and fibroblast-specific protein 1 (FSP-1). Upon stimulation with transforming growth factor beta-1, cultured hepatocytes isolated from untreated liver expressed both GFP and beta-gal with a fibroblast-like morphological change but lacked expression of other mesenchymal markers. Cells from CCl(4)-treated livers never showed double-positivity for GFP and beta-gal. All beta-gal-positive cells exhibited abundant cytoplasm, a typical morphology of hepatocytes, and expressed none of the mesenchymal markers including alpha-SMA, FSP-1, desmin, and vimentin. In liver sections of CCl(4)-treated mice, GFP-positive areas were coincident with fibrotic septa and never overlapped X-gal-positive areas.
  
  
  CONCLUSIONS
  Type I collagen-producing cells do not originate from hepatocytes. Hepatocytes in vivo neither acquire mesenchymal marker expression nor exhibit a morphological change clearly distinguishable from normal hepatocytes. Our results strongly challenge the concept that hepatocytes in vivo acquire a mesenchymal phenotype through EMT to produce the ECM in liver fibrosis.
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA, USA.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.forename: Kouichi
authors.initials: K
authors.lastname: Miura
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Osterreicher
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Melitta
authors.initials: M
authors.lastname: Penz-Osterreicher
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D004847:Epithelial Cells / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology*; D008648:Mesoderm / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D024042:Collagen Type I