2021
The Neglected Role of Bile Duct Epithelial Cells in NASH
Cadamuro M, Lasagni A, Sarcognato S, Guido M, Fabris R, Strazzabosco M, Strain AJ, Simioni P, Villa E, Fabris L. The Neglected Role of Bile Duct Epithelial Cells in NASH. Seminars In Liver Disease 2021, 42: 034-047. PMID: 34794182, DOI: 10.1055/s-0041-1739455.Peer-Reviewed Original ResearchMeSH KeywordsBile DuctsEpithelial CellsHumansInflammationInsulin ResistanceLiverLiver CirrhosisNon-alcoholic Fatty Liver DiseaseConceptsNonalcoholic fatty liver diseaseNonalcoholic steatohepatitisLiver diseaseInsulin resistancePrevalent liver diseaseBile duct epithelial cellsFatty liver diseaseSubset of patientsCommon pathogenetic mechanismDuct epithelial cellsMultiple biological effectsFibro-inflammationHepatic manifestationNAFLD patientsPortal fibrosisMetabolic syndromeBile ductDuctular reactionDisease progressionPathogenetic mechanismsLiver cancerMetabolic alterationsProgenitor cell compartmentEpithelial cellsDisease
2019
Cholangiocyte pathobiology
Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nature Reviews Gastroenterology & Hepatology 2019, 16: 269-281. PMID: 30850822, PMCID: PMC6563606, DOI: 10.1038/s41575-019-0125-y.Peer-Reviewed Original ResearchConceptsCholangiocyte pathobiologyNew disease-modifying therapiesLiver regenerationRole of cholangiocytesAdvanced liver failureDisease-modifying therapiesExtrahepatic bile ductChronic disease statesAdaptive immune responsesReactive ductular cellsLiver failureBiliary tractLiver diseaseBile ductBile productionImmune responseHepatocyte regenerationImmune systemDuctular cellsCholangiopathyDisease statesCholangiocytesEpithelial cellsAnatomic nicheRepair response
2018
β‐Catenin and interleukin‐1β–dependent chemokine (C‐X‐C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis
Kaffe E, Fiorotto R, Pellegrino F, Mariotti V, Amenduni M, Cadamuro M, Fabris L, Strazzabosco M, Spirli C. β‐Catenin and interleukin‐1β–dependent chemokine (C‐X‐C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. Hepatology 2018, 67: 1903-1919. PMID: 29140564, PMCID: PMC5906178, DOI: 10.1002/hep.29652.Peer-Reviewed Original ResearchConceptsSignal transducerΒ-cateninJanus kinase/signal transducerKinase/signal transducerActivator of transcriptionProtein kinase ATranscription 3 (STAT3) phosphorylationHepatic disease 1 (PKHD1) geneNOD-like receptorsKinase ATranscription 3Novel therapeutic avenuesGenetic diseasesNuclear translocationCognate receptorsFamily 3Nuclear factorMouse modelPKHD1Activated B cellsPhosphorylationActivatorCyst growthTherapeutic avenuesAMG 487Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy
Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M. Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy. Hepatology 2018, 67: 972-988. PMID: 28836688, PMCID: PMC5783790, DOI: 10.1002/hep.29400.Peer-Reviewed Original ResearchMeSH KeywordsAminophenolsAminopyridinesAnimalsBenzodioxolesBiliary TractCell Culture TechniquesChloride Channel AgonistsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytokinesCytoskeletonEpithelial CellsFluorescent Antibody TechniqueHumansInduced Pluripotent Stem CellsInflammationMiceMicroscopy, ConfocalPyrimidinesQuinolonesSignal TransductionSrc-Family KinasesConceptsBiliary epitheliumCystic fibrosisToll-like receptor 4Cystic fibrosis transmembrane conductance regulatorFluid secretionActivated B cells (NF-κB) activationClinical liver diseaseStrong translational potentialCause of deathB cell activationSrc kinase inhibitionFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorInflammatory changesPharmacological therapyProinflammatory changesProinflammatory chemokinesInflammation contributesLiver diseaseHuman cholangiopathiesReceptor 4Healthy controlsLiver patientsCF patientsVX-770
2017
The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma
Cadamuro M, Stecca T, Brivio S, Mariotti V, Fiorotto R, Spirli C, Strazzabosco M, Fabris L. The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1435-1443. PMID: 28757170, PMCID: PMC6386155, DOI: 10.1016/j.bbadis.2017.07.028.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsTumor reactive stromaReactive stromaMain cellular componentsDeleterious interplayCyto/chemokinesCellular componentsParacrine signalsPrognosis of cholangiocarcinomaTumor epithelial cellsCell interactionsEarly invasivenessJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenDifferent cell elementsEpithelial cellsEpithelial malignanciesTumor behaviorTumor epitheliumGrowth factorNeoplastic cellsTumor progressionCentral roleStromal componentsPathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium
Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, Fabris L. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1374-1379. PMID: 28754453, PMCID: PMC5785585, DOI: 10.1016/j.bbadis.2017.07.023.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsToll-like receptorsLiver damageCystic fibrosis-related liver diseaseInnate immunityDamage-associated molecular patternsEpithelial innate immunityPro-inflammatory behaviorBiliary epithelial cellsNumber of receptorsJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenLiver injuryLiver diseaseBile flowInflammatory processBiliary epitheliumInflammatory responsePathophysiologic implicationsReparative processesNumber of evidencesFirst defense lineCholangiocytesMolecular patternsAnimal models of biliary injury and altered bile acid metabolism
Mariotti V, Strazzabosco M, Fabris L, Calvisi DF. Animal models of biliary injury and altered bile acid metabolism. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2017, 1864: 1254-1261. PMID: 28709963, PMCID: PMC5764833, DOI: 10.1016/j.bbadis.2017.06.027.Peer-Reviewed Original ResearchConceptsBile acid metabolismBiliary injuryMouse modelAnimal modelsDistinct immune systemCholestatic liver injuryAcid metabolismJesus BanalesMarco MarzioniNicholas LaRussoPeter JansenBiliary repairLiver injuryDuctular reactionLiver repairObstructive cholestasisDisease progressionPeribiliary inflammationMain phenotypic featuresBiliary dysgenesisViral infectionImmune systemLiver homeostasisLiver phenotypeHuman setting
2016
Macrophage recruitment by fibrocystin‐defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis
Locatelli L, Cadamuro M, Spirlì C, Fiorotto R, Lecchi S, Morell C, Popov Y, Scirpo R, De Matteis M, Amenduni M, Pietrobattista A, Torre G, Schuppan D, Fabris L, Strazzabosco M. Macrophage recruitment by fibrocystin‐defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis. Hepatology 2016, 63: 965-982. PMID: 26645994, PMCID: PMC4764460, DOI: 10.1002/hep.28382.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, NeoplasmChemokinesClodronic AcidCollagenDisease Models, AnimalEpithelial CellsGenetic Diseases, InbornIntegrinsLiver CirrhosisMacrophagesMiceMyofibroblastsReceptors, Cell SurfaceSnail Family Transcription FactorsTranscription FactorsTransforming Growth Factor beta1Tumor Necrosis Factor-alphaConceptsCongenital hepatic fibrosisMacrophage recruitmentPortal hypertensionPortal fibrosisHepatic fibrosisLiver fibrosisCell dysfunctionBile duct changesRange of chemokinesLow-grade inflammationProgressive liver fibrosisDuctal plate malformationEpithelial cell dysfunctionGrowth factor-β1Biliary epithelial cellsBiliary fibrosisLiver failureMacrophage infiltratesLiver cystsDuct changesProinflammatory cytokinesPeribiliary fibrosisBiliary epitheliumDisease progressionM1 phenotype
2015
Retracted: Posttranslational regulation of polycystin‐2 protein expression as a novel mechanism of cholangiocyte reaction and repair from biliary damage
Spirli C, Villani A, Mariotti V, Fabris L, Fiorotto R, Strazzabosco M. Retracted: Posttranslational regulation of polycystin‐2 protein expression as a novel mechanism of cholangiocyte reaction and repair from biliary damage. Hepatology 2015, 62: 1828-1839. PMID: 26313562, PMCID: PMC4681612, DOI: 10.1002/hep.28138.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBile DuctsCholestasisEpithelial CellsMiceMice, Inbred C57BLProtein Processing, Post-TranslationalTRPP Cation ChannelsConceptsEndoplasmic reticulum stressorsGene expressionAutophagy pathwayExtracellular signal-regulated kinase 1/2 (ERK1/2) pathwayProtein expressionUbiquitin-like proteinSignal-regulated kinase 1/2 pathwayProteasome inhibitor MG-132HIF-1α transcriptional activityKinase 1/2 pathwayProtein kinase APC2 gene expressionPC2 expressionInhibitor MG-132Activation of ERK1/2Transient receptor potential (TRP) channel familyNonselective calcium channelPosttranslational regulationMember 1 proteinPolycystin-2Treatment of cholangiocytesKinase ATranscriptional activityChannel familyMG-132
2013
Vascular biology of the biliary epithelium
Morell CM, Fabris L, Strazzabosco M. Vascular biology of the biliary epithelium. Journal Of Gastroenterology And Hepatology 2013, 28: 26-32. PMID: 23855292, PMCID: PMC3721432, DOI: 10.1111/jgh.12022.Peer-Reviewed Original ResearchMeSH KeywordsAngiopoietinsAnimalsAutocrine CommunicationBile Duct DiseasesBile Ducts, IntrahepaticEpithelial CellsEpitheliumHumansLiverLiver Diseases, AlcoholicLiver RegenerationNeovascularization, PathologicParacrine CommunicationPlatelet-Derived Growth FactorRatsSignal TransductionVascular Endothelial Growth Factor AConceptsBile ductIntrahepatic bile ductsHepatic arteryPeribiliary plexusUnderlying molecular mechanismsArterial supplyLiver repairNormal organ physiologyLiver pathophysiologyVascular cell typesPathophysiological settingsVascular structuresStrong associationVascular biologyDifferent vascular cell typesCholangiocytesAngiogenic signalsLiver developmentCell typesMolecular mechanismsOrgan physiologyDuctAssociationCross talk
2012
Cyclic AMP/PKA‐dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin‐2 defective mice treated with sorafenib
Spirli C, Morell CM, Locatelli L, Okolicsanyi S, Ferrero C, Kim AK, Fabris L, Fiorotto R, Strazzabosco M. Cyclic AMP/PKA‐dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin‐2 defective mice treated with sorafenib. Hepatology 2012, 56: 2363-2374. PMID: 22653837, PMCID: PMC3460040, DOI: 10.1002/hep.25872.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, HormonalBenzenesulfonatesBile DuctsCaspase 3Cell ProliferationCells, CulturedCyclic AMP-Dependent Protein KinasesCystsDrug Therapy, CombinationEpithelial CellsKi-67 AntigenLiver DiseasesMAP Kinase Signaling SystemMiceMice, KnockoutNiacinamideOctreotidePhenylurea CompoundsPhosphorylationProtein Kinase InhibitorsProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-rafPyridinesSorafenibTRPP Cation ChannelsConceptsRaf-1Cell proliferationB-RafPhosphorylated ERKRaf kinase activitySignal-regulated kinase 1/2 pathwayRAF inhibitorsCyclic adenosine monophosphateRaf/MEK/ERKCyst growthDefective miceKinase 1/2 pathwayParadoxical activationCAMP/PKAMEK/ERKPolycystin-2Kinase AKinase activityWT cellsDependent activationERK1/2 phosphorylationInhibitor 14Epithelial cellsAdenosine monophosphateERK
2011
Loss of CFTR Affects Biliary Epithelium Innate Immunity and Causes TLR4–NF-κB—Mediated Inflammatory Response in Mice
Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Loss of CFTR Affects Biliary Epithelium Innate Immunity and Causes TLR4–NF-κB—Mediated Inflammatory Response in Mice. Gastroenterology 2011, 141: 1498-1508.e5. PMID: 21712022, PMCID: PMC3186841, DOI: 10.1053/j.gastro.2011.06.052.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Bacterial AgentsBile DuctsCholagogues and CholereticsCholangitisColitisCytokinesDextran SulfateDisease Models, AnimalEpithelial CellsHEK293 CellsHumansImmunity, InnateInflammation MediatorsKeratin-19Leukocyte Common AntigensLipopolysaccharidesMiceMice, Inbred C57BLMice, Inbred CFTRMice, KnockoutNeomycinNF-kappa BPhosphorylationPolymyxin BSrc-Family KinasesTime FactorsToll-Like Receptor 4TransfectionUrsodeoxycholic AcidConceptsCFTR KO miceBiliary epitheliumCystic fibrosisPortal inflammationBiliary damageInflammatory responseInnate immunityGut-derived bacterial productsTLR4 inhibitor TAK-242Toll-like receptor 4Cystic fibrosis transmembrane conductance regulatorInhibitor TAK-242Wild-type littermatesActivation of NFNuclear factor κBOral neomycinTLR4-NFTAK-242Liver damagePathogenetic roleBile flowDuctular reactionReceptor 4Cytokine secretionUrsodeoxycholic acidPolycystic Liver Diseases: Congenital Disorders of Cholangiocyte Signaling
Strazzabosco M, Somlo S. Polycystic Liver Diseases: Congenital Disorders of Cholangiocyte Signaling. Gastroenterology 2011, 140: 1855-1859.e1. PMID: 21515270, PMCID: PMC3109236, DOI: 10.1053/j.gastro.2011.04.030.Peer-Reviewed Original ResearchMeSH KeywordsBiliary TractCystsDisease ProgressionEpithelial CellsGenetic Predisposition to DiseaseHumansLiver DiseasesSignal TransductionConceptsPolycystic liver diseaseLiver cyst formationClinical featuresLiver diseaseMultiple cystsDisease progressionBiliary epitheliumLiver parenchymaProgressive enlargementCongenital diseaseCyst formationCholangiocyte physiologyCongenital disorderPotential targetGenetic defectsDiseaseProgressionDisordersInheritance patternSignalingIntracellular organellesDifferent entitiesTherapyKidneyPathwayEpithelial–Mesenchymal Interactions in Biliary Diseases
Fabris L, Strazzabosco M. Epithelial–Mesenchymal Interactions in Biliary Diseases. Seminars In Liver Disease 2011, 31: 011-032. PMID: 21344348, PMCID: PMC3729030, DOI: 10.1055/s-0031-1272832.Peer-Reviewed Original ResearchConceptsReactive cholangiocytesChemo/cytokinesBile secretory functionLiver repair mechanismsDe novo expressionDifferent mesenchymal cell typesMost cholangiopathiesCell typesPortal fibrosisPortal infiltratesLiver diseaseBiliary diseaseUnderlying molecular mechanismsBiliary epitheliumDifferent etiologiesLiver repairSecretory functionNovo expressionCholangiopathyBiliary cellsCentral mechanismsMesenchymal cell typesMesenchymal propertiesEndothelial cellsGrowth factor
2009
Diferentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation
Strazzabosco M, Fiorotto R, Melero S, Glaser S, Francis H, Spirli C, Alpini G. Diferentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation. Hepatology 2009, 50: 244-252. PMID: 19444869, PMCID: PMC2738985, DOI: 10.1002/hep.22926.Peer-Reviewed Original ResearchMeSH KeywordsAdenylyl CyclasesAnimalsBile DuctsEpithelial CellsGene Expression RegulationIsoenzymesMaleRatsRats, Sprague-DawleyConceptsSoluble adenylyl cyclaseAdenylyl cyclasesGene expressionAC isoformsCyclic adenosine monophosphateAC gene expressionDifferent tissue specificitiesGroup of enzymesAdenylyl cyclase isoformsTissue specificityCholangiocyte secretionCyclase isoformsIsoformsSAC inhibitorIsohydric changesAdenylyl cyclaseIsoform expressionSACS geneReal-time polymerase chain reactionGenesAdenosine monophosphateAC8ExpressionCAMP levelsCAMP production
2007
Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development
Fabris L, Cadamuro M, Libbrecht L, Raynaud P, Spirlì C, Fiorotto R, Okolicsanyi L, Lemaigre F, Strazzabosco M, Roskams T. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology 2007, 47: 719-728. PMID: 18157837, DOI: 10.1002/hep.22015.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factorHepatic arteryAngiogenic growth factorsBile ductAngiopoietin-1Tie-2Growth factorAngiopoietin-2VEGFR-1Endothelial cellsMural cellsCognate receptorsIntrahepatic bile ductsClose anatomical relationshipFetal human liverDifferent gestational agesEndothelial growth factorDifferent maturational stagesGestational ageHuman liver developmentImmunohistochemical expressionDuctal plateEpithelial expressionPortal vasculatureArtery
2001
Ductular morphogenesis and functional polarization of normal human biliary epithelial cells in three-dimensional culture
Ishida Y, Smith S, Wallace L, Sadamoto T, Okamoto M, Auth M, Strazzabosco M, Fabris L, Medina J, Prieto J, Strain A, Neuberger J, Joplin R. Ductular morphogenesis and functional polarization of normal human biliary epithelial cells in three-dimensional culture. Journal Of Hepatology 2001, 35: 2-9. PMID: 11495037, DOI: 10.1016/s0168-8278(01)00078-2.Peer-Reviewed Original ResearchConceptsCollagen gel cultureHuman biliary epithelial cellsEpithelial cellsGel cultureGrowth factorHuman hepatocyte growth factorThree-dimensional cultureBiliary epithelial cellsThree-dimensional aggregatesNormal human biliary epithelial cellsFoetal bovine serumMorphogenesisCell typesAnion exchanger 2Hepatocyte growth factorFunctional polarizationFunctional differentiationFunctional markersExchanger 2Monolayer culture systemCentral lumenPhenotypic markersCollagen gelsNumber of aggregatesCulture system
2000
Characterization and Isolation of Ductular Cells Coexpressing Neural Cell Adhesion Molecule and Bcl-2 from Primary Cholangiopathies and Ductal Plate Malformations
Fabris L, Strazzabosco M, Crosby H, Ballardini G, Hubscher S, Kelly D, Neuberger J, Strain A, Joplin R. Characterization and Isolation of Ductular Cells Coexpressing Neural Cell Adhesion Molecule and Bcl-2 from Primary Cholangiopathies and Ductal Plate Malformations. American Journal Of Pathology 2000, 156: 1599-1612. PMID: 10793072, PMCID: PMC1876925, DOI: 10.1016/s0002-9440(10)65032-8.Peer-Reviewed Original ResearchConceptsDuctal plate malformationNeural cell adhesion moleculeReactive ductulesDuctular cellsLiver diseaseKi-67Cell adhesion moleculeDuctal plateChronic cholestatic liver diseaseDifferent chronic liver diseasesAdhesion moleculesReactive bile ductulesProliferation marker Ki-67Chronic liver diseaseCholestatic liver diseaseDuctal plate cellsBcl-2Different gestational agesDuctular reactive cellsGestational ageLKM-1Neuroendocrine featuresHEA 125Cirrhotic liverImmunohistochemical expressionPathophysiology of the intrahepatic biliary epithelium
Strazzabosco M, Spirlì C, Okolicsanyi L. Pathophysiology of the intrahepatic biliary epithelium. Journal Of Gastroenterology And Hepatology 2000, 15: 244-253. PMID: 10764023, DOI: 10.1046/j.1440-1746.2000.02091.x.Peer-Reviewed Original ResearchConceptsIntrahepatic biliary epitheliumBiliary epitheliumIntrahepatic bile duct epitheliumChronic cholestatic disorderBile duct epitheliumCholangiocyte functionBasic disease mechanismsPortal inflammationBiliary atresiaGastrointestinal hormonesCholestatic disordersPathophysiological pointBiliary treeCholangiocyte pathophysiologyImmune regulationPharmacological approachesNormal epitheliumCholangiocyte proliferationCholangiopathyDuct epitheliumInfectious agentsImportant causeBile acidsCystic fibrosisImmunoglobulin A.
1998
Purinergic regulation of acid/base transport in human and rat biliary epithelial cell lines
Zsembery Á, Spirlì C, Granato A, LaRusso N, Okolicsanyi L, Crepaldi G, Strazzabosco M. Purinergic regulation of acid/base transport in human and rat biliary epithelial cell lines. Hepatology 1998, 28: 914-920. PMID: 9755225, DOI: 10.1002/hep.510280403.Peer-Reviewed Original ResearchConceptsCholangiocyte cell lineNHE activityPurinergic agonistsBiliary epithelial cell lineExtracellular ATPCell linesIntracellular cyclic adenosine monophosphate (cAMP) concentrationsBiliary HCO3- secretionRat cholangiocyte cell lineCyclic adenosine monophosphate concentrationsAdenosine receptor agonistsBiliary epithelial cellsMz-ChA-1 cellsAdenosine monophosphate concentrationsSynergistic stimulatory effectApical administrationEpithelial cell lineReceptor agonistP2Y2 receptorPurinergic receptorsBile volumePharmacological profileApical Cl- channelsBasolateral administrationHCO3- secretion