The crucial role of cholangiocytes in cholangiopathies

Abstract

Cholangiopathies are diseases involving the intrahepatic biliary tree. They appear to involve, chronic inflammation of the bile ducts, which can lead to the development of bile duct cholestasis, proliferation/ductopenia, biliary fibrosis, and malignant transformation. Sustained stimulatory insults to biliary epithelial cells can induce a ductular reaction, which has a key role in the initiation and progression of cholangiopathies. The epithelial-mesenchymal interaction between reactive cholangiocytes and mesenchymal cells with the inflammatory infiltrates plays a major role in this pathogenesis. Cytokines, chemokines, growth factors and morphogens mediate these interactions in an autocrine or paracrine manner. The main hepatic myofibroblasts (MFs) in cholangiopathies originate from portal fibroblasts. Hepatic stellate cells and fibrocytes also transform into MFs. Whether cholangiocytes or hepatocytes are a source of MFs via the epithelial-mesenchymal transition (EMT) remains a matter of controversy. Although there have been numerous indirect findings supporting the theory of a cholangiocyte EMT in human tissues, recent studies using lineage tracing methods have demonstrated strong evidence against the EMT. Understanding the pathogenic mechanisms involved in cholangiopathies can allow for better-targeted anti-fibrotic therapies in animal models. Before anti-fibrotic therapies can translate into clinical trials, improved monitoring of the fibrotic progression of cholangiopathies and an accurate assessment regarding the effectiveness of the proposed treatments must be achieved.

Keywords: Anti-fibrotic therapy; Cholangiopathies; Epithelial-mesenchymal interaction; Epithelial-mesenchymal transition.

Fig. 1

A putative pathogenic model of cholangiopathies. The initial insult to biliary epithelial cells and the host response may induce an inflammatory reaction. It generally resolves with the resolution of the insulting agent to the biliary tree. However, the persistence of insults to the biliary tree and/or derangement of the host response will lead to chronic inflammation, cholestasis, and bile duct proliferation and ductopenia. Ultimately, chronic cholangiopathies progress to biliary fibrosis and/or malignant transformation.

Fig. 2

Interactions between reactive cholangiocytes and other liver cells in cholangiopathies. Reactive cholangiocytes interact with mesenchymal cells (e.g., HSCs, portal fibroblasts, myofibroblasts, and fibrocytes), endothelial cells, macrophages, and lymphocytes by exchanging paracrine or autocrine signals. CTGF, connective tissue growth factor; VEGF, vascular endothelial growth factor; TGF, transforming growth factor; Wnt, wingless; HGF, hepatocyte growth factor; HSC, hepatic stellate cell; PDGF, platelet-derived growth factor; Hh, Hedgehog; Ang, angiopoietin; ET, endothelin; NO, nitric oxide; SDF-1, stromal cell-derived factor 1; BM, basement membrane; IFN, interferon; IL, interleukin; TNF, tumor necrotic factor; MCP, monocyte chemotactic protein; FGF, fibroblast growth factor; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition.