title: Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis.
abstract: Currently, hepatic stellate cells (HSC) are thought to be the major fibrotic precursor cells that transdifferentiate to fibrogenic, extracellular matrix producing myofibroblasts in inflammatory liver tissue upon transforming growth factor-beta (TGF-beta) signaling, whereas hepatocytes are thought to respond with apoptosis to this cytokine. Starting out from in vitro experiments with primary hepatocyte cultures and immortalized AML-12 cells, TGF-beta signaling in this cell type was assessed and apoptosis was found to be only a minor effect. Instead, hepatocytes undergo epithelial mesenchymal transition (EMT), a physiological process in embryogenesis and of relevance for cancerous cell transformation. In injured liver, however, this process contributes to the promotion of fibrosis. Already after a few days of culture, hepatocytes lose their epithelial honeycomb-like shape towards a fibroblast-like phenotype. We could demonstrate by microarray analysis that stimulation of hepatocytes with TGF-beta regulates the expression of genes involved in EMT and fibrosis. Among these were, for example, Snail, a known mediator of EMT, and connective tissue growth factor (CTGF), a strong inducer of fibrosis. In a mouse model, hepatocyte-specific overexpression of Smad7 was able to blunt a fibrogenic response after CCl(4) intoxication. These results emphasize the dynamic nature of liver fibrosis, challenge the paradigm of HSC as a crucial source of liver myofibroblasts and hint towards a prominent role for hepatocytes in liver fibrogenesis.
authors.affiliation: Molecular Alcohol Research in Gastroenterology, II, Medical Clinic, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nadja M
authors.initials: NM
authors.lastname: Meindl-Beinker
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology*; D008648:Mesoderm / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta