The dynamic biliary epithelia: molecules, pathways, and disease

Abstract

Cholangiocytes, the cells lining bile ducts, are a heterogenous, highly dynamic population of epithelial cells. While these cells comprise a small fraction of the total cellular component of the liver, they perform the essential role of bile modification and transport of biliary and blood constituents. From a pathophysiological standpoint, cholangiocytes are the target of a diverse group of biliary disorders, collectively referred to as the cholangiopathies. To date, the cause of most cholangiopathies remains obscure. It is known, however, that cholangiocytes exist in an environment rich in potential mediators of cellular injury, express receptors that recognize potential injurious insults, and participate in portal tract repair processes following hepatic injury. As such, cholangiocytes may not be only a passive target, but are likely directly and actively involved in the pathogenesis of cholangiopathies. Here, we briefly summarize the characteristics of the reactive cholangiocyte and cholangiocyte responses to potentially injurious endogenous and exogenous molecules, and in addition, present emerging concepts in our understanding of the etiopathogenesis of several cholangiopathies.

Fig. 1. The role of cholangiocytes in cholangiopathies

Cholangiocytes recognize potential insults (endogenous or exogenous) and respond through the upregulation of proinflammatory mediators. These features are a component of the intricate crosstalk between a variety of resident and recruited cells, including hepatocytes, progenitor cells, fibroblasts and leukocytes, in an attempt to repair the epithelium. In most cases, the proinflammatory response and injury/damage to the biliary tree is resolved. However, in the genetically susceptible individual, perpetuation of the repair response results in progressive liver injury and a persistent inflammatory response, leading to chronic inflammation of the bile ducts and ultimately, disease.

Fig. 2. Cholangiocytes exist in an environment rich of potential mediators of cellular injury

Through enterohepatic circulation: (1) the liver is exposed to bacterially derived products (PAMPs), xenobiotics and endogenous mediators of inflammation (DAMPs). Portal blood flows into hepatic sinusoids, where a variety of resident and recruited cells can recognize and respond to these potential insults. Ultimately, hepatocytes take up, modify, and excrete these molecules into the canaliculus. Canalicular bile percolates through the biliary tree where cholangiocytes recognize and react to these potential insults through the increased release and response to repair associated chemokines/cytokines, growth factors, and morphogens, initiating both autocrine and paracrine signaling cascades (2). A more comprehensive understanding of the role of the gut in hepatic function and the molecular networks mediating injury induced growth and repair, as well as the cholangiocyte epigenetic phenomena, and the genetic variation (3) that contribute to the perpetuation of this phenotype and sequelae, including fibrogenesis and carcinogenesis, will undoubtedly open avenues for potential therapeutic approaches.