HGF/c-Met signaling in hepatocytes protects against progression of chronic liver fibrosis

HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. Treatment with HGF accelerates the resolution of fibrotic liver lesions in experimental animal models. To formally address the importance of c-Met signaling in hepatocytes in the context of chronic liver damage, we have used a model of chronic liver fibrosis in hepatocyte specific Metfl/fl;Alb-Cre±conditional knockout mice (KO). CCl4 was administrated biweekly over 4 weeks (injury phase) and animals were followed for the next 4 weeks (healing phase). Macroscopic and microscopic changes during both phases were monitored by IHC. Activation of hepatic stellate cells (HSC) was estimated by a-SMA. Expression levels of fibrogenic molecules were evaluated by RT-PCR and WB. Time dependent global transcriptomic changes from whole livers and isolated hepatocytes were examined using microarrays.Loss of HGF/c-Met signaling in hepatocytes resulted in increased liver damage characterized by decreased hepatocyte proliferation, progressive accumulation of HSCs, increased collagen deposit and delayed fibrinolysis. Global transcriptome analysis demonstrated upregulation of key fibrogenic molecules, such as Tgf-β and Pdgf-β, paralleled by decreased expression of genes important for cell cycle and stress response. While the latter could be attributed to c-Met deficiency in hepatocytes, major pro-fibrotic signaling originated from non-parenchymal cell compartments, as revealed by cell type specific gene expression signatures. Additionally, chemotactic and inflammatory cytokines were upregulated in Metfl/fl;Alb-Cre±hepatocytes leading to impaired recruitment of mononucleated cells and reduced phagocytosis. These results indicate that lack of c-Met signaling in hepatocytes disrupts balance between extracellular matrix production and degradation and establish a protective role for c-Met induced factors in hepatocyes against the development of fibrotic liver disease.

CCL4 - HGF - Hepatic Stellate Cells - cMET - liver Fibrosis