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Review
, 16 (5), 269-281

Cholangiocyte Pathobiology

Affiliations
Review

Cholangiocyte Pathobiology

Jesus M Banales et al. Nat Rev Gastroenterol Hepatol.

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.

Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Ductal bile formation.
Bile produced by hepatocytes (primary or hepatic bile) is delivered into bile ducts. The Canals of Hering provide the continuum between the hepatocyte canaliculus and the ductules or cholangioles, the small bile ducts and the large bile ducts in which hepatic bile is modified to become ductal bile. A hepatic progenitor cell (HPC) niche is also thought to reside at the interface of the cells lining the Canals of Hering and the hepatocyte plate. Active biliary epithelial transport of electrolytes and solutes occurs in small and large bile ducts and determines the vectorial water movement (that is, absorption or secretion) across cholangiocytes, thus altering ductal bile composition and flow. Adapted with permission from REF., Elsevier.
Fig. 2
Fig. 2. Molecular mechanisms regulating biliary secretion and absorption.
Cholangiocytes regulate the flow, composition and pH of the primary bile generated at the canaliculi of hepatocytes through different mechanisms, including the absorption of bile acids (BAs), glucose and amino acids (step 1) and the secretion of bicarbonate (HCO3 −) and water (step 2). Secretin (step 3) stimulates the apical insertion of intracellular vesicles containing anion exchange protein 2 (AE2), cystic fibrosis transmembrane conductance regulator (CFTR) and aquaporin 1 (AQP1), resulting in chloride secretion through CFTR that is exchanged with bicarbonate via AE2. This bicarbonate generates osmotic force for the movement of water via AQP1. Biliary bicarbonate secretion creates the biliary bicarbonate umbrella that protects cholangiocytes against the damaging effect of toxic protonated BAs (BAHs). Hormones such as bombesin and vasoactive intestinal peptide (VIP) stimulate biliary bicarbonate secretion, whereas somatostatin, gastrin and dopamine inhibit this process. Extracellular nucleotides and nucleosides, via P2Y receptors, and acetylcholine (ACh) also promote baseline and secretin-stimulated bicarbonate secretion, respectively (step 4). The cholangiocyte primary cilium acts as a (step 5) mechanosensor (via polycystin 1 (PC1)), (steps 6–8) chemosensor (via G protein-coupled bile acid receptor 1 (TGR5), P2Y purinoceptor 2 (P2Y2) and extracellular vesicle (EV)) and (step 9) osmosensor (via transient receptor potential channel vanilloid subfamily 4 (TrpV4)), detecting signals in bile and subsequently modifying cell biology and bile flow and composition. AC5, adenylyl cyclase type 5; InsP3, inositol 1,4,5-trisphosphate; PKA, protein kinase A; PKC, protein kinase C; TMEM16A, transmembrane protein 16F.
Fig. 3
Fig. 3. Potential sources of cholangiocytes in development and liver regeneration.
a | Cholangiocytes develop via differentiation from hepatoblasts in response to developmental morphogens. b | Cholangiocyte homeostasis is based on self-replication of pre-existing mature cholangiocytes. c | Cholangiocyte regeneration occurs through an accelerated replication in response to regenerative hormones, growth factors and cytokines. d | Cholangiocyte differentiation from hepatic progenitor cells can occur during biliary injury and repair after reactivation of developmental pathways.
Fig. 4
Fig. 4. Ductular reaction and ductular-reactive cells.
Extensive research has identified many of the morphogenetic mechanisms and molecules involved in the complex signalling and cellular crosstalk network of biliary repair. This crosstalk involves many cytokines, chemokines and signalling molecules. Most of these factors have both paracrine and autocrine effects and can act on multiple cell types. For example, vascular endothelial growth factor (VEGF) can autocrinally stimulate cholangiocyte proliferation, as the VEGF2 receptor is also expressed in cholangiocytes, but VEGF has paracrine effects on the endothelial cells (stimulation of neoangiogenesis) and stimulates mesenchymal cells. At the same time, IL-6 can stimulate cholangiocyte growth and the recruitment of neutrophils. The coexistence of reactive ductular cells and a rich mesenchymal and immune infiltrate constitutes the ductular reaction. The signals between the different infiltrating cell types are integrated into morphogenetic cues enabling cholangiocytes to re-create the biliary architecture owing to the re-expression of Wnt, Hedgehog and Notch signalling. CCL2, CC-chemokine ligand 2; CTGF, connective tissue growth factor; CXCL, CXC-chemokine ligands; DAMPs, damage-associated molecular patterns; EGF, epidermal growth factor; HGF, hepatocyte growth factor; IGF1, insulin-like growth factor 1; nitric oxide (NO); PAMPs, pathogen-associated molecular patterns; PDGFBB, platelet-derived growth factor B homodimer B; TGFβ2, transforming growth factor-β2; TNF, tumour necrosis factor.
Fig. 5
Fig. 5. Key aspects of cholangiocyte immunobiology.
Quiescent cholangiocytes secrete antimicrobial molecules into bile (such as immunoglobulin A (IgA)) and express a range of innate immune receptors (for example, Toll-like receptors (TLRs) and NOD-like receptors (NLRs)) that recognize conserved pathogen-associated molecular patterns. The antigen-presenting capacities of cholangiocytes remain disputed regarding class II and T cell receptor (TCR) interactions, but CD1d and MR1 on cholangiocytes have been shown to effectively present lipid antigens and riboflavin derivatives to natural killer T (NKT) cells and mucosa-associated invariant T (MAIT) cells. Activated cholangiocytes engage in extensive paracrine crosstalk with cells of the immune system, including monocytes and macrophages, neutrophil granulocytes and T cells. Furthermore, autocrine signalling loops (for example, IL-6 signalling) provide further stimulation to augment and modify the activated cholangiocyte phenotype. CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CXCL, CXC-chemokine ligand; CXC-chemokine receptor; ICAM1, intercellular adhesion molecule 1; iTCR, invariant T cell receptor; LPS, lipopolysaccharide; MMP9, matrix metallopeptidase 9; PD-L1, programmed cell death 1 ligand 1; TH17 cell, T helper type 17 cell; TNF, tumour necrosis factor; Treg cell, regulatory T cell; VCAM1, vascular cell adhesion molecule 1.

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