Central Journal of and Clinical Research

Mini Review *Corresponding author Massimiliano.Cadamuro, School Of Medicine, University of Milan-Bicocca, Via Cadore, 48; 20900 Monza, Italy, The Multitasking Behavior of Tel: 02-6448-8089; Email:

Submitted: 07 October 2015 Cholangiocytes in the Reaction to Accepted: 11 November 2015 Published: 13 November 2015 Liver Damage ISSN: 2379-0830 Copyright Massimiliano Cadamuro1,2*, Mario Strazzabosco1,3 and Luca © 2015 Cadamuro et al. Fabris2,3 OPEN ACCESS 1 School of Medicine and Surgery, University of Milan-Bicocca, Italy 2Department of Molecular Medicine, University of Padova School of Medicine, Italy 3Department of Digestive Disease Section, Yale University School of Medicine, USA Keywords • Cholangiocytes Abstract • Ductular reaction • Liver repair Cholangiocytes are the epithelial cells lining the bile ducts. Within the wide • Portal fibrosis functional heterogeneity displayed by cholangiocytes through the different portions of the biliary tree, ductular cells of the finest peripheral ramifications, in strict contact with the canals of Hering, possess a reactive phenotype. This phenotype is essential for generating the hepatic reparative system, a multicellular complex including epithelial, mesenchymal and inflammatory cells, whereby they extensively communicate by mutually exchanging a variety of paracrine signals. Herein, we review the most recent insights on the molecular mechanisms underlying the ability of reactive cholangiocytes to orchestrate the development of this sort of ‘multiethnic society’, whose persistent activation is a critical determinant of liver disease progression.

INTRODUCTION of its etiology, and lead to the ductular reaction, which is closely associated with the activation and proliferation, at different Cholangiocytes are the epithelial cells that line the biliary degrees, of the hepatic progenitor cell (HPC) compartment, by tree, a complex system of ducts divided into an intrahepatic and which it is directed. an extrahepatic tract, connecting the liver to the intestine. After the , the other liver epithelial cell, cholangiocytes The hepatic reparative system represent the second most common cell type in the liver (about Ductular reaction is a stereotyped histological lesion 5% of the total liver cell mass). Similar to hepatocytes and their common to different forms of chronic liver injury underpinning ‘functional regionalization’ through the Rappaport’s acinus the generation of the ‘hepatic reparative system’ (Figure 1). This zones, cholangiocytes display a wide range of functions, which markedly vary upon their topographic localization within the biliary system [1,2]. In Table 1 the current nomenclature of cholangiocytes lining different bile ductal structures in normal and diseased conditions is outlined. While cholangiocytes lining the larger ducts are essentially involved in absorptive and secretory activities by which they modify the primary bile secreted by hepatocytes, cholangiocytes of the smallest bile ductules, abutting the canals of Hering (terminal ductules), possess peculiar and sophisticated biological properties, such as plasticity, reactivity and stemness, enabling them to orchestrating the reaction to liver damage. Plasticity is the ability to modify the native epithelial phenotype by acquiring some traits typically expressed by mesenchymal cells, reactivity is the propensity to Figure 1 Tissue section of a patient with primary sclerosing whilst stemness is the attitude to behave as progenitor cells with cholangitis immunostained for the biliary marker EpCAM (HEA-125), theset in potential motion the ability inflammatory to differentiate response bidirectionally elicited by liver into damage, both showing the activation and expansion of the different cell elements and cholangiocyte lineages [3,4]. All of these features of the hepatic reparative system, encompassing HPC (black arrows), DRC (red arrows), and IHBC (white asterisks). M: 200x. can be variably activated in response to liver damage, regardless

Cite this article: Cadamuro M, Strazzabosco M, Fabris L (2015) The Multitasking Behavior of Cholangiocytes in the Reaction to Liver Damage. J Liver Clin Res 2(3): 1017. Cadamuro et al. (2015) Email: Central is dynamic, multicellular, morpho-functional complex, where ductular epithelial cells, developing as irregular strings along in the ECM composition aimed at favoring reciprocal cell-cell the margins of the portal tract, acquire a ‘reactive’ phenotype interactions.leading to the In activationfact, generation of a fibrogenicof the hepatic program reparative and complex changes characterized by the de novo expression of a variety of cytokines, chemokines, growth factors and angiogenic factors coupled with and subsequently, their spreading as DRC along the boundaries a rich receptor equipment [1,3,5]. These phenotypic changes withfirst requires the lobular the parenchymadetachment toof HPC reach from areas the whereby periportal they niche can enable ductular reactive cells (DRC) to establish intense paracrine critically interact with the other cooperating cell elements, communications with multiple stromal cell types, including several factors are emerging to play a crucial function amenable Ductular reaction is the mirror of the severity of liver disease, ofmostly targeted mesenchymal intervention. and inflammatory cells. During this process, sincemyofibroblasts, several studies inflammatory indicate a closecells correlation and endothelial between cells. the Neural cell adhesion molecule (NCAM)/Polysialic Acid: expansion of DRC and the extent of hepatocellular and/or biliary The neo-expression of the neuroendocrine marker NCAM injury. In fact, the correlation between the expansion of the DRC particular relevance for HPC spreading and DRC generation. demonstrated in several liver pathologies such as Non-alcoholic NCAMand its is post-transcriptionala surface glycoprotein modification mediating homo is a mechanism(cell-cell) and of fattyand HPCliver populationdisease (NAFLD) and the [6], stagechronic of liver portal diseases fibrosis [7], has chronic been heterotypic (cell-matrix) interactions during the development viral hepatitis [8], and genetic cholangiopathies [9]. of several epithelial tissues, including the nervous system, lung Epithelial cell elements engaged in the hepatic and gut. In the liver, NCAM is transiently expressed during reparative system fetal development by the embryonic structures from which the intrahepatic bile ducts originate, i.e. the ductal plates. NCAM As previously stated, HPC and DRC are the main effector cells could also act as a Polysialic acid (PolySia) carrier, given its driving the response to liver damage in both chronic and acute ability to bind up to 100 PolySia residues. Following conjugation disease conditions. HPC are small cells, single or in small clumps, with PolySia, NCAM changes its adhesive properties to anti- adhesive due to the size of the multiple PolySia chains and their niche, where they lay in close contact with the canals of Hering, high hydrophilic content and may behave as a sort of “lube oil” with an oval shape and scant cytoplasm, confined to the periportal the boundary line between hepatocytes and cholangiocytes. [17,18]. Therefore, once bound to PolySia, the anti-adhesive HPC are bipotential cells, able to differentiate into either the NCAM allows HPC to acquire migratory properties, by which biliary or the hepatocyte lineage [10]. In humans, differentiation they leave the periportal niche and reach the margins of the towards hepatocytes occurs via intermediate hepato-biliary cells portal tract, where, as DRC, they can cross talk with other NCAM- (IHBC), whereas differentiation towards the biliary lineage leads to the formation of DRC. DRC are epithelial cells organized into reparative response. The cooperation among the different cell irregularly shaped, tube-like structures, tightly anastomosed typesexpressing populating cell types, the portal mainly microenvironment fibroblasts, to mount depends the hepatic on the each other, often without a recognizable lumen. HPC, IHBC and interplay between ligands and receptors reciprocally expressed by DRC and mesenchymal-derived cell types. As mentioned In addition to the stem cell markers c-Kit and CD34, HPC express above, DRC may secrete a wide range of soluble factors, including DRC can be identified by a specific immunophenotype (Table 1). neuroendocrine features, together with cholangiocyte and growth factors, such as angiopoietin-1, connective tissue growth hepatocyte markers. In contrast, DRC display the expression of factor (CTGF), endothelin-1, platelet-derived growth factor the typical biliary lineage markers, [10-13], in conjunction with (PDGF)-BB, PDGF-DD, and vascular endothelial growth factor the de novo expression of several neural markers [14,10,13], (VEGF)-A] [19-22], cytokines and chemokines (i.e. CINC, IL-6, whilst the epithelial membrane antigen (EMA), a marker of mature biliary , is down-regulated [13]. IL-8, MCP-1, Osteopontin (OPN), TGFβ2, TNFα) [3,5], and other Molecular factors regulating the development of the species) [5, 23-25]. Thanks to these huge secretory activities, DRCpro-inflammatory orchestrate the molecules recruitment, (nitric activation oxide and and reactiveproliferation oxygen of hepatic reparative system According to the classical view, the HPC compartment cells, immune cells), with which they build the complex machinery is activated only when the proliferative ability of mature responsiblemultiple cell for types liver (myofibroblasts,repair and regeneration. macrophages, endothelial hepatocytes is compromised because of the severity of the necro Osteopontin (OPN): In the extensive cross talk centered on DRC, OPN is a mediator attracting increasing interest. OPN is a parenchymal loss [15]. However, this is true only in experimental pleiotropic factor acting as either cytokine or ECM protein able conditions,inflammatory since liver in damage, human which liver diseases,precludes HPC them activation to replace may the to direct cell motility and adhesion, as well as the response of occur even in milder forms of liver damage, regardless of the level of inhibition of the hepatocyte replication. The factors OPN was originally found to be frequently over-expressed in triggering the HPC activation and then regulating the expansion hepatocellularT-lymphocytes and carcinoma, macrophages where in it inflammation appears to beand involved immunity. in of the DRC compartment are an area of deep and continuously the modulation of tumoral cell growth, invasion and metastasis. evolving investigation. Interactions with the extracellular Two recent studies demonstrated OPN over-expression by DRC matrix (ECM) components are likely pivotal determinants of in different mouse models of chronic liver injury with evolution these mechanisms [16]. This process depends upon a complex -/- mice treated with thioacetamide or interplay between paracrine signals released by HPC and DRC ligation [26], and C57BL/6 feed with 3,5,-Diethoxycarbonyl-1,4- to fibrosis, Opn

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Table 1: Morphology and immunophenotype of the biliary structures observed in normal and diseased . Structures Immunophenotype Morphology (K7) Normal Liver

K7, K8, K18, K19, EpCAM (HEA125), EMA, OV-6, Canals of Hering HNF1 , HNF6

β

K7, K8, K18, K19, EpCAM (HEA125), EMA, OV-6, Bile Ducts HNF1 , HNF6

β

Diseased Liver

Biliary markers: K7, K19, EpCAM (HEA125), OV-6 Hepatocyte markers: K8, K18, Hepar-1, and Hepatic Progenitor Cells (HPC) Stem cell markers: CD34, c-Kit Neuralα-fetoprotein markers: Chrom-A, NCAM

Biliary markers: K7, K19, EpCAM (HEA125), OV-6 Hepatocyte markers: K8, K18 Ductular Reactive Cells Stem cell markers: c-Kit (DRC) Neural markers: muscarinic acetylcholine receptors M1-3, and M5, Chrom-A, NCAM

Biliary markers: K7, EpCAM (HEA125), OV-6 Intermediate Hepato- Hepatocyte markers: Biliary Cells (IHBC) K18 Neural markers: Chrom-A,α-1-antitrypsin, NCAM albumin, K8;

modulate external signal transduction into cells by interacting these experimental models, OPN is a critical player promoting the activationdihydrocollidine of the HPC or Methionine-choline compartment and its deficient expansion diets leading [27]. Into (integrins), and growth factors. This cytokine is fundamental for the development of ductular reaction. This mechanism is relevant with ECM components (fibronectin), cell surface glycoproteins hepatic reparative response thanks to its ability to synergize with the modulation of the fibrogenic response occurring during the responsefor the progression associated ofwith liver a reduced fibrosis; extent in fact, of OPNHPC andneutralization DRC. obtained with OPN-specific aptamers resulted in a milder fibrotic particular.TGFβ1. Moreover, In a recent CTGF study may [22] promote performed proliferation, in a CTGF-KO migration mouse Connective tissue growth factor (CTGF)/CCN2 and CCN1: modeland adhesion (Ctgfk/k ),of CTGF several was inflammatory found to stimulate cell types, activation macrophages of the HPC in Another driving factor recently emerged in ductular reaction is CTGF. CTGF is a member of the cysteine-rich, secreted, glycoprotein expressed by several epithelial cell types in response heparin-binding CCN protein family (also called CCN2) able to niche by interacting with αvβ6 integrin. αvβ6 integrin is a surface

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Down-regulation of CTGF led to a reduced number of HPC and cytokines mediating the cross talk within the ductular reaction to injury, which locally activates the latent form of TGFβ1. haveThe been harmful recently effects pinpointed on cholangiocytes in a mouse of model the pro-inflammatory of injury. Similar to CTGF/CCN2, another member of the CCN family, (BALB/c mice infected with rhesus rotavirus), a disease with CCN1,consequently, was recently to a decreased found to befibrosis involved deposition in promoting following ductular liver a marked hyperplasia of the bile ducts. The treatment of these reaction. CCN1 is a matricellular protein able to modulate several mice with IL-33, a cytokine predominantly secreted in biliary cellular activities, such as proliferation, senescence, apoptosis, atresia with profound mitogen effects on different epithelial migration and adhesion. CCN1 stimulated Jag1 expression and cell types, stimulated the hepatic accumulation of non-cytotoxic activated the Jag/Notch signaling in cholangiocytes through its innate lymphoid cells type 2 (ILC2), the subtype of immune cells responsible for a Th2 response [36]. IL-33-recruited ILC2 secreted cholangiocyte proliferation in vitro, a response prevented by in the portal environment high amounts of IL13, which in turn, interaction with the αvβ3/αvβ5 integrins. This led to an increased promoted and sustained the proliferation of cholangiocytes and the activation of the repair mechanisms through the activation of modelseither treatment in which CCN1with specificexpression siRNA was against deleted, CCN1, or the or CCN1 by using gene the YAP and AKT pathways [37]. Therefore, in this biliary injury differentharbored αinactivating or β integrin mutations sub-units. in the Furthermore, binding site usingto integrins, mouse model, the IL-33/ILC2/IL-13 axis promoted epithelial repair. the ductular reaction induced by bile duct ligation results However, induction of this circuit in mice with constitutive markedly impaired [28]. activation of AKT and YAP in bile ducts was oncogenic since it induced cholangiocarcinoma with liver metastases [37]. Functional effects on cholangiocytes exerted by the inflammatory microenvironment; insights from disease (CFLD) are liver disease conditions characterized by an experimental models of biliary injury Congenital hepatic fibrosis (CHF) and the liver microenvironment generated by a ‘reactive’ biliary phenotype causedevolving by scarring genetic course, defects. which In CHF, is driven the bygenetic the inflammatory mutation in evolutionThe brisk to pro-inflammatory cirrhosis, but also response the further mounted progression by ductular to liverreaction malignancies, is pivotal to such not only as hepatocellular promoting liver carcinoma fibrosis and or biliary cysts progressively enlarge in association with a dense and cholangiocarcinoma. Once recruited, a mutual exchange of fibrocystin (FPC), a ciliary protein expressed by cholangiocytes, paracrine and autocrine signals between DRC and the recruited In a mouse model of CHF, harboring a genetic inactivation of theworsening gene encodingfibrosis and for a FPCsmolder (Pkhd1 portaldel4/del4 inflammatory infiltrate. cells, mostly macrophages, were recruited by FPC-defective mediatorsinflammatory released cells within and fibroblaststhe portal microenvironment, sustain and expand IL-6 the is cholangiocytes due to the secretion of the) chemokines [38], inflammatory CXCL1, aductular prevalent reaction. cytokine, Among which the stronglypro-inflammatory stimulates and cholangiocyte pro-fibrotic receptor IL6R expressed by DRC in conjunction with the co- [39,40].CXCL10, InCXCL12 turn, induced cholangiocytes by an over-activation responded to of macrophages- β-catenin, a receptorproliferation gp130, [29]. activates The interaction the p42/44 between MAPK IL-6 signaling, and its the specific main signalling system emerging as a novel regulator of inflammation pro-proliferative pathway in cholangiocytes, in concert with . Targeting macrophage the phosphorylation of JAK1 and STAT3 and consequently the recruitmentderived cytokines in vivo (TNF-α by clodronate and TGF-β) was by up-regulating clinically relevant the αvβ6 as activation of the PI3K/AKT pathway regulating the escape from integrin, which locally activated TGFβ1 cell death [30,31]. The cooperation between these two pathways hypertension and also the growth of the biliary cysts [41]. These is a fundamental mechanism sustaining to the growth of DRC. datait reduced indicate the that extent in CHF, of fibrosis, recruited the macrophages development stimulate of portal cytokines with relevant effects on DRC functions is nitric oxide Another molecular factor activated by pro-inflammatory transmembranefibrosis along with conductance the expansion regulator of the biliary (CFTR), cysts a [41]. protein In a originallymouse model known of CFLD as driver(CF-KO ofmice), the defects Cl-transport in the acrosscystic fibrosis ductal synthase(NO). The (iNOS) elevated isoform, concentrations the enzyme in the mainly portal responsible area of IL-1β, for epithelial cell membranes, led in cholangiocytes to an aberrant theIL-6, transformation TNFα, and IFNγ of L-arginine may activate in NO, the in inducible the colangiocytes. nitric oxide A pathogenic effect of NO on cholangiocyte functions is dual. On secretion of several pro-inflammatory cytokines and chemokines - reactive, hypersecretory phenotype displayed by cholangiocytes one side, it induces cholestasis by reducing the secretion of Cl (CXCL1, G-CSF, IL-1α, IL-6, LIX, MCP-1, and MIP-2). In CFLD, the and HCO3- mediated by CFTR and AE2, through inhibition of the is induced by the activation of the Toll-like receptor (TLR)-4/ adenilyl cyclase activity, which decreases the cyclic adenosine NF-kB signalling. In addition to stimulating biliary proliferation monophosphate (cAMP) intracellular levels [24,32,33]. On the activation of both neutrophils (CXCL1, G-CSF, MIP-2 and LIX) other, NO may stimulate neoplastic transformation of the biliary (IL-1α, IL-6), these mediators promoted the recruitment and epithelium by inducing DNA damages or inhibiting the controlling and macrophages (MCP-1). Interestingly, in CF-KO mice the functions of DNA repair proteins, in particular of the 8-oxo- interference with the TLR4/NF-kB axis led in vivo reduction in the extent of the ductular reaction [42]. deoxiguanine DNA glycosilase 1 [34]. This mechanism might , to a significant be relevant in primary sclerosing cholangitis, a biliary disease CONCLUSIONS at high risk of developing cholangiocarcinoma, where iNOS up- regulation in cholangiocytes is particularly pronounced [24,35]. Following acute and chronic injury, the liver stereotypically reacts mounting a reparative response driven by HPC activation

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Cite this article Cadamuro M, Strazzabosco M, Fabris L (2015) The Multitasking Behavior of Cholangiocytes in the Reaction to Liver Damage. J Liver Clin Res 2(3): 1017.

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