Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology

Abstract

Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases.

Keywords: Biliary tree; cholangiocytes; liver; neuroendocrine regulation; proliferation.

Figure 1

Schematic illustration of the neuroendocrine compartment. Top. Immunohistochemistry for CK19, a specific marker of biliary epithelium in liver section from normal rat. Bar =40 µm. In normal condition cholangiocytes are quiescent (black arrows) but since they are target cells in several chronic cholestatic liver diseases (termed cholangiopathies), they start to proliferate as happen for example in the experimental model of bile ducts ligation (bottom. Immunohistochemistry for CK19 in liver section from BDL rat in which is evident the high proliferation of the biliary ducts (black arrows). Bar =40 µm. Proliferating cholangiocytes acquire the phenotype of neuroendocrine cells, and start to secrete different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation (on the right in red) or apoptosis (on the left in green) trying to reestablish the balance between proliferation/loss of cholangiocytes.