| dc.description.abstract | Cholangiopathies, such as primary sclerosing cholangitis (PSC), are progressive liver diseases that target the cholangiocyte and are characterized by inflammation, proliferation, fibrosis, and senescence, for which only limited treatment options are available. Studies have shown microRNA 16 (miR-16) plays a prominent role in profibrotic liver diseases in addition to fibroblast growth factor 1 (FGF1), which contributes to hepatic fibrosis through the activation of hepatic stellate cells (HSCs). However, the role of miR-16 in conjunction with FGF1 in the progression of cholangiopathies such as PSC, is unknown. Therefore, the goal of this study was to evaluate the role of FGF1 in the progression of biliary damage and assess its correlation with miR-16 in mouse models of liver pathology. Male multi-drug resistant 2 (Mdr2-/-) or bile-duct ligated (BDL) C57BL/6 mice (12 weeks old) and corresponding controls were treated with either an FGF1 agonist, FGF receptor antagonist (AZD4547), or FGF1 monoclonal antibody (Mdr2-/- and control). We measured: (i) FGF1, FGF receptors (FGFR), miR-16, and angiogenesis via immunofluorescence (IF), quantitative polymerase chain reaction (qPCR), or enzyme-linked immunosorbent assay in liver sections, isolated cholangiocytes, and serum; (ii) biliary proliferation by immunohistochemistry (IHC) for cytokeratin-19 and qPCR for proliferation genetic markers Ki67 and proliferating cell nuclear antigen (PCNA) in isolated cholangiocytes; (iii) inflammatory markers by qPCR and IHC in total liver homogenates and liver sections; (iv) biliary senescence via senescence associated β galactosidase, IF, and qPCR; and (v) fibrosis using Sirius Red and qPCR for collagen type 1 alpha 1 (Col11) and alpha smooth muscle actin (SMA). In vitro, we treated cholangiocytes and HSCs with FGF1 monoclonal antibody and measured genes of proliferation/senescence. We found significant increases in FGF1/FGFR expression, biliary proliferation, angiogenesis, liver inflammation, and fibrosis in Mdr2-/- mice with corresponding decreases in miR-16. However, Mdr2-/- mice treated with either an FGFR antagonist or anti-FGF1 mAb displayed a significant reduction in liver fibrosis, senescence, inflammation, angiogenesis, and biliary proliferation. We have demonstrated that disruption of FGF1/FGFR signaling ameliorates fibrosis, proliferation, senescence, angiogenesis, and inflammation in a mouse model of cholestasis, and disruption or activation of the FGF1/FGFR pathway correlates with increased/decreased miR-16 gene expression. In conclusion, the FGF1/FGFR signaling pathway may provide novel therapeutic targets in the fight against PSC. | |
