Cholangiopathies are a heterogeneous group of chronic liver diseases caused by different types of injury targeting the biliary epithelium, such as genetic defects and immune-mediated attacks. Notably, most cholangiopathies are orphan, thereby representing one of the major gaps in knowledge of the modern hepatology. A typical hallmark of disease progression in cholangiopathies is portal scarring, and thus development of effective therapeutic approaches would aim to hinder cellular and molecular mechanisms underpinning biliary fibrogenesis. Recent lines of evidence indicate that macrophages, rather than more conventional cell effectors of liver fibrosis such as hepatic stellate cells and portal fibroblasts, are actively involved in the earliest stages of biliary fibrogenesis by exchanging a multitude of cues with cholangiocytes, which promote their recruitment from the circulating compartment owing to a senescent or an immature epithelial phenotype. Two cholangiopathies, namely primary sclerosing cholangitis and congenital hepatic fibrosis, are paradigmatic of this mechanism. This review summarizes current understandings of the cytokine and extracellular vesicles-mediated communications between cholangiocytes and macrophages typically occurring in the two cholangiopathies to unveil potential novel targets for the treatment of biliary fibrosis.
Metabolic syndrome (MetS) is a common condition closely associated with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). Recent meta-analyses show that MetS can be prodromal to intrahepatic cholangiocarcinoma (iCCA) development, a liver tumor with features of biliary differentiation characterized by dense extracellular matrix (ECM) deposition. Since ECM remodeling is a key event in the vascular complications of MetS, we aimed at evaluating whether MetS patients with iCCA present qualitative and quantitative changes in the ECM able to incite biliary tumorigenesis. In 22 iCCAs with MetS undergoing surgical resection, we found a significantly increased deposition of osteopontin (OPN), tenascin C (TnC), and periostin (POSTN) compared to the matched peritumoral areas. Moreover, OPN deposition in MetS iCCAs was also significantly increased when compared to iCCA samples without MetS (non-MetS iCCAs, n = 44). OPN, TnC, and POSTN significantly stimulated cell motility and the cancer-stem-cell-like phenotype in HuCCT-1 (human iCCA cell line). In MetS iCCAs, fibrosis distribution and components differed quantitatively and qualitatively from non-MetS iCCAs. We therefore propose overexpression of OPN as a distinctive trait of MetS iCCA. Since OPN stimulates malignant properties of iCCA cells, it may provide an interesting predictive biomarker and a putative therapeutic target in MetS patients with iCCA.
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