Functional and structural features of cholangiocytes in health and disease

Abstract

Cholangiocytes are the epithelial cells that line the bile ducts. Along the biliary tree, two different kinds of cholangiocytes exist; small and large cholangiocytes. Each type has important differences in their biological role in physiological and pathological conditions. In response to injury, cholangiocytes become reactive and acquire a neuroendocrine-like phenotype with the secretion of a number of peptides. These molecules act in an autocrine/paracrine fashion to modulate cholangiocyte biology and determine the evolution of biliary damage. The failure of such mechanisms is believed to influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. Therefore, the understanding of mechanisms regulating cholangiocyte response to injury is expected to foster the development of new therapeutic options to treat biliary diseases. In the present review, we will discuss the most recent findings in the mechanisms driving cholangiocyte adaptation to damage, with particular emphasis on molecular pathways that are susceptible of therapeutic intervention. Morphogenic pathways (Hippo, Notch, Hedgehog), which have been recently shown to regulate biliary ontogenesis and response to injury, will also be reviewed. In addition, the results of ongoing clinical trials evaluating new drugs for the treatment of cholangiopathies will be discussed.

Keywords: Biliary Epithelium; Primary Biliary Cirrhosis; Primary Sclerosing Cholangitis.

Figure 1

Overview of cholangiocyte role in biliary functions. (A) Intrahepatic bile ducts are lined by both large and small cholangiocytes. Under physiologic conditions, cholangiocytes (large cholangiocytes preferentially) modify ductal bile by a sequence of secretory and absorptive processes mediated by membrane exchangers. This modification mainly leads to the formation of bicarbonate rich bile. Cholangiocytes also secrete vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), which are regulated by microRNA 125b and let-7a, respectively. (B) The formation of bicarbonate rich bile is enhanced by stimulation with secretin and adenosine 3′,5′-cyclic monophosphate (cAMP), which increase in response to liver insult. The liver behaves as a neuroendocrine compartment in response to injury and starts to respond to hormones and peptides in an autocrine as well as paracrine manner. Liver injury is subsequently followed by large cholangiocyte proliferation under the influence of these factors (neurotransmitters, gastrointestinal peptides, steroids). The large, but not the small, bile ducts express secretin receptor (SR) and somatostatin receptor 2 (SSTR2) and respond to secretin and somatostatin. Biliary hyperplasia results in cholestasis, which further results in human biliary disorders such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Occasionally, in response to specific events injury or drug administration, small cholangiocytes proliferate by a d-myo-inositol 1,4,5-triphosphate (IP3)-mediated signaling pathway, often to compensate for the lack of large cholangiocyte proliferation and thus maintain the biliary mass. Bottom: Isolation of small (right), approximately 9-μm diameter, and large (left), approximately 13-μm diameter, cholangiocytes from human SV-40 transformed cholangiocytes (H69 cells). Small and large human cholangiocytes were purified by counterflow elutriation followed by immunoaffinity purification. Original magnification: ×800.