3A\C); no immunoreactivity for FGF1 was observed for HSCs in liver sections co\stained with desmin (Fig

3A\C); no immunoreactivity for FGF1 was observed for HSCs in liver sections co\stained with desmin (Fig. presence of hepatic fibrosis, biliary proliferation, inflammation, senescence, and angiogenesis. Targeting the FGF1 and miR\16 axis may provide therapeutic options in treating cholangiopathies such as PSC. Abstract Cholangiocytes are the target cells FRAP2 in various rodent models of biliary damage, such as extrahepatic bile duct ligation (BDL) and multidrug resistance 2 knockout (Mdr2 ?/? , a model of primary sclerosing cholangitis [PSC]), which are associated with O6BTG-octylglucoside enhanced biliary senescence with concomitant release of senescence\associated secretory factors (SASPs, such as transforming growth factor\1 [TGF\1]) activating hepatic stellate cells (HSCs) by paracrine pathways.( 1 ) PSC is usually a progressive liver disease characterized by inflammation, fibrosis, and narrowing of the bile ducts. O6BTG-octylglucoside The progressive destruction of intrahepatic bile ducts eventually leads to cirrhosis and end\stage liver failure, necessitating liver transplantation, O6BTG-octylglucoside which is usually often the only, but not optimal, treatment option, as PSC can recur after liver transplantation.( 2 ) During PSC pathogenesis, cholangiocytes show increased proliferation and proinflammatory signaling, which leads to an increase in hepatobiliary fibrosis, inflammatory infiltration, biliary remodeling, and cellular senescence.( 3 ) There is growing information around the regulation of biliary damage and liver fibrosis in PSC( 4 ); however, there are limited and controversial data around the role of fibroblast growth factor (FGF) signaling in the modulation of PSC phenotypes.( 5 ) FGF1 belongs to more than 20 homologs that participate in a diverse range of functions in numerous cell types throughout the body through its conversation with one or more of the four FGF receptor subtypes (FGFR1\4).( 6 ) FGFs can modulate various physiological functions such as cellular proliferation, migration, tissue remodeling, and DNA synthesis via receptor activation.( 7 ) FGF1 and FGF2 regulate hepatic fibrosis( 8 ) through the activation of HSCs, which express FGFR1\4.( 9 ) FGF1 also plays a role in fetal hepatic development by inducing cytokeratin\19 (CK\19) expression in hepatic progenitor cells.( 10 ) MicroRNAs (miRs) are noncoding RNA molecules that regulate many gastrointestinal pathologies, including cancer, autoimmune disorders, and fibrotic diseases.( 11 ) Research continues to expand on the various roles of miR\16 across multiple liver pathologies, such as the activation of HSCs.( 12 ) Previous studies have exhibited a potential link/feedback between FGF signaling and miR\16 in several pathologies, such as mesothelioma and angiogenic signaling in endothelial cells.( 13 , 14 ) However, the role of miR\16 in the progression of PSC is usually undefined. In the present study, we aimed to determine (1) the immunoreactivity/expression of FGFR1\4 and FGF1 and FGF1 serum and biliary levels in BDL and Mdr2 ?/? mice and human PSC samples; (2) the effects of recombinant human FGF1 (rhFGF1) and anti\FGF monoclonal antibody (mAb) on biliary damage/senescence and liver inflammation/fibrosis in BDL and Mdr2 ?/? mice; and (3) whether the effect of the FGF1/FGFR axis on liver phenotypes is associated with changes in the expression of miR\16. Materials and Methods Materials Immunohistochemical supplies and reagents for tissue culture were obtained from Thermo Fisher Scientific (Waltham, MA). Animals were treated with a rhFGF1 protein (GF002; MilliporeSigma, Burlington, MA), a mouse FGF acidic/FGF1 neutralizing antibody (AF4686; R&D Systems, Minneapolis, MN),( 15 ) or a pan FGFR antagonist (AZD4547, ab216311; Abcam, Burlingame, CA).( 16 ) Total RNA was isolated using the to water and standard mouse chow. C57BL/6 mice underwent BDL as described( 17 ) with minipump implantation occurring after ligation. Both WT and BDL mice received minipump implantation made up of either rhFGF1 (100 ng/kg body weight.