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The Dynamic Biliary Epithelia: Molecules, Pathways, and Disease

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The Dynamic Biliary Epithelia: Molecules, Pathways, and Disease Review The dynamic biliary epithelia: Molecules, pathways, and disease ⇑ Steven P. O’Hara, James H. Tabibian, Patrick L. Splinter, Nicholas F. LaRusso Department of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States Summary well as bioactive molecules present in bile, including endogenous (bile acids, lipids, nucleotides) and exogenous (microbially- Cholangiocytes, the cells lining bile ducts, are a heterogenous, derived, xenobiotic) molecules that modify cholangiocyte func- highly dynamic population of epithelial cells. While these cells tion and/or phenotype. These molecules, some potentially injuri- comprise a small fraction of the total cellular component of the ous, can induce cellular responses affecting repair and liver, they perform the essential role of bile modification and remodeling of the biliary epithelium. transport of biliary and blood constituents. From a pathophysio- logical standpoint, cholangiocytes are the target of a diverse group of biliary disorders, collectively referred to as the cholangi- Key Points opathies. To date, the cause of most cholangiopathies remains • Cholangiocytes, the cells lining bile ducts, are a obscure. It is known, however, that cholangiocytes exist in an heterogenous, highly dynamic population of epithelial environment rich in potential mediators of cellular injury, cells that recognize and respond to insult and/or injury express receptors that recognize potential injurious insults, and (i.e., cholangiocyte reactivity) participate in portal tract repair processes following hepatic injury. As such, cholangiocytes may not be only a passive target, • The molecular mechanisms regulating the but are likely directly and actively involved in the pathogenesis of cholangiocyte response to exogenous and cholangiopathies. Here, we briefly summarize the characteristics endogenous insults is an active area of research that of the reactive cholangiocyte and cholangiocyte responses to continues to provide insight into the innate immune, potentially injurious endogenous and exogenous molecules, and proinflammatory and reparative function of this in addition, present emerging concepts in our understanding of epithelium the etiopathogenesis of several cholangiopathies. • Cholangiocytes are the target of a diverse group Ó 2012 European Association for the Study of the Liver. Published of biliary disorders of different etiopathogenesis, by Elsevier B.V. All rights reserved. collectively referred to as cholangiopathies • In a subset of cholangiopathies, the cholangiocyte response to insult or injury and the resultant Introduction communication with resident and recruited cells, implicates the cholangiocyte as not only a target, The intrahepatic bile ducts form a complex three-dimensional but also likely a central and active candidate in the network of conduits lined by a single layer of specialized epithe- initiation and propagation of disease lial cells, the cholangiocytes. In addition to their role in bile mod- ification and transport, cholangiocytes actively sense and respond Cholangiocytes vary in size, shape, and function along the biliary to the inflammatory environment associated with liver injury, as tree (i.e., are heterogeneous [1]), and animal models of biliary injury show that the nature of the biliary insult can determine which subpopulation of cholangiocytes is affected [2,3]. For Keywords: Cholangiocytes; Cholangiopathy; Biliary; Reactivity; Repair. example, in response to acute injury, large cholangiocytes (i.e., Received 24 May 2012; received in revised form 1 October 2012; accepted 10 October those from larger ducts) proliferate and maintain normal biliary 2012 ⇑ Corresponding author. Address: Mayo Clinic, 200 First Street, SW, Rochester, homeostasis. In contrast, chronic injury promotes increased pro- MN 55905, United States. Tel.: +1 507 284 1006; fax: +1 507 284 0762. liferation of both large and small ducts and induces a reparative E-mail address: [email protected] (N.F. LaRusso). process associated with ductular changes that may include not Abbreviations: PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; only expansion of existing ducts, but also induction of liver pro- IBD, inflammatory bowel disease; UCDA, ursodeoxycholic acid; PRR, pathogen recognition receptor; TLR, Toll-like receptor; NOD, nucleotide-binding oligomer- genitor cells (i.e., ductular reaction) (reviewed in [4]). This heter- ization domain; PAMP, pathogen-associated molecular pattern; LPS, lipopolysac- ogeneity of response is consistent with and may account for the charide; CFTR, cystic fibrosis transductance regulator; DAMP, damage-associated differential distribution of cholangiopathies along the biliary tree. molecular pattern; ncRNA, non-coding RNA; miRNA, microRNA; NF-kB, nuclear Cholangiocytes are the target of a diverse group of biliary factor kappa B; GWAS, genome-wide association studies; HLA, human leukocyte disorders of different etiologies, collectively referred to as antigen. Journal of Hepatology 2013 vol. 58 j 575–582 Review cholangiopathies [5]. Here we present a pathogenic framework for a subset of these disorders, namely idiopathic (i.e., primary Insult sclerosing cholangitis-PSC) and immune-mediated (i.e., primary biliary cirrhosis-PBC) cholangiopathies, focusing primarily on Reactive cholangiocyte responses to constituents of bile. At the center of cholangiocyte this conceptual framework is the concept of the ‘‘activated’’ or ‘‘reactive’’ cholangiocyte, characterized by an enhanced proin- flammatory response including the secretion of chemokines, Proinflammatory cytokines, growth factors, and morphogens that promote microenvironment Genetic increased cholangiocyte proliferation, and biliary remodeling. susceptibility These cholangiocytes participate in an intricate cross-talk between a variety of resident and recruited cells, including hepa- Loss of tolerance. Cellular crosstalk Resolution tocytes, progenitor cells, hepatic stellate cells, portal fibroblasts, Persistent repair and and leukocytes (primarily macrophages, neutrophils, and lym- response repair response phocytes). In yet to be fully characterized genetically susceptible individuals, the exaggeration or derangement of cholangiocyte Cholangiopathy: responses to bioactive molecules and the ensuing reparative pro- Progressive biliary Epigenetic • cholestasis injury/ modifications?/ • ductopenia cesses are likely an essential component of disease evolution. inflammation senescence? • fibrosis Identification of the nature and origin of the insults and a more • neoplasia comprehensive understanding of the molecular pathways regu- lating reactivity and repair processes throughout the biliary tree, are important and active areas of research that will likely identify Fig. 1. The role of cholangiocytes in cholangiopathies. Cholangiocytes recog- new therapeutic targets and approaches. nize 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 cholangiopathies the epithelium. In most cases, the proinflammatory response and injury/damage to the biliary tree is resolved. However, in the genetically susceptible individual, The cholangiopathies are a group of disorders that can be orga- perpetuation of the repair response results in progressive liver injury and a nized into several broad categories: immune-mediated, drug- or persistent inflammatory response, leading to chronic inflammation of the bile ducts and ultimately, disease. toxin-induced, infectious, genetic, ischemic and idiopathic. How- ever, these categories overlap and more than one pathogenic cytes from the diseased gut are recruited to the hepatobiliary mechanism may be operative in a given cholangiopathy. Despite tract in response to adhesion molecules and chemokines that their heterogeneity, the cholangiopathies have in common a are normally restricted to the gut [8]. number of cholangiocyte-associated processes that may contrib- As with most cholangiopathies, particularly in the early ute to their pathogenesis, including pro-inflammatory signaling, stages, PBC and PSC generally affect distinct regions of the biliary innate-immune responses, proliferation, and differentiation. tree. Bile duct destruction in PBC is limited to small interlobular These cholangiocyte processes, particularly in genetically suscep- and septal bile ducts, while in PSC, the larger intra- and extrahe- tible individuals, may become disrupted and set the stage for patic bile ducts are preferentially affected. Although both PSC and other phenomena including aberrant biliary remodeling, chole- PBC increase the risk of hepatocellular carcinoma, unlike PBC, PSC stasis, and fibrosis (Fig. 1). is also a major risk factor for cholangiocarcinoma, occurring in Two of the cholangiopathies, PSC and PBC, are rare but impor- approximately 0.5% per year, and does not require a background tant causes of chronic liver disease. Both are characterized by of cirrhosis [9,10]. Optimal cancer surveillance in PSC patients is chronic inflammation of the bile ducts and follow a course that an area of ongoing investigation. generally progresses to biliary cirrhosis, portal hypertension, With respect to pharmacotherapy, the bile acid, ursodeoxy- and liver failure. From
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