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Transforming growth factor‐β and hepatocyte transdifferentiation in liver fibrogenesis
Author(s) -
MeindlBeinker Nadja M,
Dooley Steven
Publication year - 2008
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2007.05297.x
Subject(s) - hepatic stellate cell , ctgf , transdifferentiation , transforming growth factor , cancer research , microbiology and biotechnology , hepatocyte , myofibroblast , fibrosis , hepatocyte growth factor , epithelial–mesenchymal transition , extracellular matrix , transforming growth factor beta , growth factor , biology , pathology , medicine , stem cell , downregulation and upregulation , in vitro , receptor , biochemistry , gene
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‐β (TGF‐β) 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‐β 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‐β 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.