Abstract
Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.
Key points
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Cholangiocytes are epithelial cells lining the intrahepatic and extrahepatic bile ducts; they are heterogeneous in size and function and contribute to bile composition and flow by solute transport processes.
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Cholangiocytes contribute to liver regeneration, especially when hepatocyte regeneration is compromised, as is often the case in human chronic liver diseases.
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Cholangiocytes can become activated and participate in inflammation by secreting chemokines and cytokines and can also directly modulate the biology of myofibroblasts, the cell type responsible for collagen deposition within the liver.
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Cholangiocytes can become senescent and participate in the senescence-associated secretory phenotype, a cell fate also characterized by cytokine generation and release.
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Cholangiocytes participate in hepatic immunobiology, particularly by expressing Toll-like receptors (TLRs), contributing to immunoglobulin A (IgA) biology, and by cellular crosstalk with the innate and adaptive immune system.
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Cholangiocytes are damaged in a variety of human liver diseases termed the cholangiopathies, which are in need of optimized therapies and represent a current unmet need in clinical medicine.
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Acknowledgements
J.M.B. has received grant support from the Spanish Ministries of Economy and Competitiveness (FIS PI15/01132, FIS PI18/01075 and Miguel Servet Programme CON14/00129) co-financed by ‘Fondo Europeo de Desarrollo Regional’ (FEDER); ISCIII (CIBERehd), Spain; BIOEF (Basque Foundation for Innovation and Health Research); EiTB Maratoia BIO15/CA/016/BD; the Department of Health of the Basque Country (2017111010); and the Scientific Foundation of the Spanish Association Against Cancer (AECC). The authors also acknowledge the US National Institutes of Health grants DK63947 (G.J.G.); DK057993, DK084567 and DK24031 (N.F.L.); and DK100575 and DK113339 (R.C.H.). G.J.G., N.F.L. and R.C.H. further acknowledge support from the Carlos Family Foundation and the Mayo Clinic. M.S. has recieved support from the US National Institutes of Health Grants DK079005, DK096096 and DK34989, the Silvio O. Conte Digestive Diseases Research Core Centers and PSC Partners Seeking a Cure.
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Banales, J.M., Huebert, R.C., Karlsen, T. et al. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol 16, 269–281 (2019). https://doi.org/10.1038/s41575-019-0125-y
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DOI: https://doi.org/10.1038/s41575-019-0125-y
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