2017
Liver myofibroblasts of murine origins express mesothelin: Identification of novel rat mesothelin splice variants*
Fausther M, Lavoie E, Dranoff JA. Liver myofibroblasts of murine origins express mesothelin: Identification of novel rat mesothelin splice variants*. PLOS ONE 2017, 12: e0184499. PMID: 28898276, PMCID: PMC5595315, DOI: 10.1371/journal.pone.0184499.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsLiver myofibroblastsStellate cellsFibrosis progressionLiver diseasePortal fibroblastsMesothelial cellsChronic cholestatic liver diseaseProgressive scar formationChronic liver diseaseCholestatic liver diseaseNormal mesothelial cellsSplice variantsEffector cellsOrgan failureCell surface moleculesHepatic fibrosisMyofibroblast proliferationMyofibroblast functionScar formationMesothelinPolyclonal ratCell markersMyofibroblastsCholangiocarcinoma cellsExtracellular vesicles carry microRNA‐195 to intrahepatic cholangiocarcinoma and improve survival in a rat model
Li L, Piontek K, Ishida M, Fausther M, Dranoff JA, Fu R, Mezey E, Gould SJ, Fordjour FK, Meltzer SJ, Sirica AE, Selaru FM. Extracellular vesicles carry microRNA‐195 to intrahepatic cholangiocarcinoma and improve survival in a rat model. Hepatology 2017, 65: 501-514. PMID: 27474881, PMCID: PMC5258762, DOI: 10.1002/hep.28735.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBile Duct NeoplasmsCarcinogenesisCell MovementCholangiocarcinomaDisease Models, AnimalDown-RegulationExtracellular VesiclesFibroblastsHumansImmunohistochemistryMaleMicroRNAsRandom AllocationRatsRats, Inbred F344Real-Time Polymerase Chain ReactionSensitivity and SpecificitySurvival RateTransfectionTumor Cells, CulturedTumor MicroenvironmentConceptsExtracellular vesiclesMiR speciesCancer cellsCancer-associated fibroblastsFibroblasts-derived extracellular vesiclesMiR-195Rat modelMicroRNA speciesQuantitative reverse transcription polymerase chain reactionCCA cellsSpeciesCancer developmentCancer fibroblastsHuman cholangiocarcinomaMiR contentReverse transcription-polymerase chain reactionNovel therapeuticsFibroblastsCentral roleSize of cancerVesiclesCellsPolymerase chain reactionMicroRNA-195Cancer microenvironment
2015
Establishment and Characterization of Rat Portal Myofibroblast Cell Lines
Fausther M, Goree JR, Lavoie ÉG, Graham AL, Sévigny J, Dranoff JA. Establishment and Characterization of Rat Portal Myofibroblast Cell Lines. PLOS ONE 2015, 10: e0121161. PMID: 25822334, PMCID: PMC4378927, DOI: 10.1371/journal.pone.0121161.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsPortal fibroblastsMyofibroblast cell lineLiver fibrosisCell linesAlpha 1Alpha-smooth muscle actinMyofibroblast marker alpha-smooth muscle actinScar-forming myofibroblastsSmooth muscle actinMesenchymal cell markersNTPDase2/CD39L1Lecithin retinol acyltransferaseStellate cellsCollagen alpha 1Cholangiocyte proliferationMetalloproteinases-1Muscle actinTissue inhibitorAdult rat liverCell markersCholangiocarcinoma cellsCulture activationRetinol acyltransferaseFunctional studies
2012
Activated hepatic stellate cells upregulate transcription of ecto-5′-nucleotidase/CD73 via specific SP1 and SMAD promoter elements
Fausther M, Sheung N, Saiman Y, Bansal MB, Dranoff JA. Activated hepatic stellate cells upregulate transcription of ecto-5′-nucleotidase/CD73 via specific SP1 and SMAD promoter elements. AJP Gastrointestinal And Liver Physiology 2012, 303: g904-g914. PMID: 22899823, PMCID: PMC3469697, DOI: 10.1152/ajpgi.00015.2012.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsPortal fibroblastsLiver myofibroblastsLiver fibrosisStellate cellsMyofibroblastic hepatic stellate cellsQuiescent hepatic stellate cellsActivated hepatic stellate cellsCD73 gene expressionCD73-deficient miceRegulation of CD73Experimental liver fibrosisPromising molecular targetCD73 geneLiver diseaseAdenosine generationNovel cellular markerAntifibrotic therapyExperimental fibrosisFibrous septaRate-limiting enzymeCD73 proteinMyofibroblastic differentiationFibrotic liverAdenosine production
2011
Coexpression of ecto-5′-nucleotidase/CD73 with specific NTPDases differentially regulates adenosine formation in the rat liver
Fausther M, Lecka J, Soliman E, Kauffenstein G, Pelletier J, Sheung N, Dranoff JA, Sévigny J. Coexpression of ecto-5′-nucleotidase/CD73 with specific NTPDases differentially regulates adenosine formation in the rat liver. AJP Gastrointestinal And Liver Physiology 2011, 302: g447-g459. PMID: 22135310, PMCID: PMC3287391, DOI: 10.1152/ajpgi.00165.2011.Peer-Reviewed Original ResearchConceptsRat liverRecombinant rat enzymeDistinct fibroblast populationsP2 receptor agonistsSmooth muscle cellsNTPDase2/CD39L1Vascular endothelial cellsFibrotic rat liverCD73 protein expressionSpecific biochemical propertiesPortal fibroblastsReceptor agonistP2 receptorsNormal rat liverFibrotic conditionsPortal spacesInhibitor ADPAdenosine formationMuscle cellsCD73Endothelial cellsTriphosphate diphosphohydrolaseFormation of adenosineProtein expressionEctonucleotidases
2009
Transcriptional regulation of IL-6 in bile duct epithelia by extracellular ATP
Yu J, Sheung N, Soliman EM, Spirli C, Dranoff JA. Transcriptional regulation of IL-6 in bile duct epithelia by extracellular ATP. AJP Gastrointestinal And Liver Physiology 2009, 296: g563-g571. PMID: 19136380, PMCID: PMC2660176, DOI: 10.1152/ajpgi.90502.2008.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsAntibodiesBile DuctsCalciumCalcium SignalingCell Line, TransformedCell Line, TumorCyclic AMPEpithelial CellsExtracellular SpaceFibroblastsHumansImmunoblottingInterleukin-6MaleMutagenesis, Site-DirectedPromoter Regions, GeneticRatsRats, Sprague-DawleyReceptors, Purinergic P2Response ElementsRNA, MessengerSignal TransductionTranscriptional ActivationConceptsBile duct epitheliumIL-6IL-6 transcriptionDuct epitheliumLiver injuryCAMP response elementP2Y11 receptorInflammatory cytokines IL-6Extracellular ATPIL-6 upregulationUse of agonistsRat bile duct epitheliaCytokines IL-6IL-6 releaseIL-6 promoter activityIL-6 mRNAExtracellular ATP actsCalcium agonistP2Y receptorsPharmacological profileHepatic responseCalcium-dependent fashionExtracellular nucleotidesCytosolic calciumPurinergic signalsIntracellular calcium signals regulate growth of hepatic stellate cells via specific effects on cell cycle progression
Soliman EM, Rodrigues MA, Gomes DA, Sheung N, Yu J, Amaya MJ, Nathanson MH, Dranoff JA. Intracellular calcium signals regulate growth of hepatic stellate cells via specific effects on cell cycle progression. Cell Calcium 2009, 45: 284-292. PMID: 19131107, PMCID: PMC3018528, DOI: 10.1016/j.ceca.2008.11.006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcium SignalingCalcium-Calmodulin-Dependent Protein Kinase Type 2Cdc25 PhosphatasesCell CompartmentationCell CycleCell NucleusCell ProliferationChelating AgentsCytosolEgtazic AcidEnzyme InhibitorsG2 PhaseHepatocytesHumansIntracellular SpaceParvalbuminsPhosphorylationProtein TransportRatsSubcellular FractionsConceptsHepatic stellate cellsLiver fibrosisStellate cellsImmortalized human hepatic stellate cellsHSC growthHuman hepatic stellate cellsRat hepatic stellate cellsPrimary rat hepatic stellate cellsIntracellular calcium signalsCdc25C phosphorylationPharmacological therapyCalmodulin kinase IIImportant mediatorCell cycle progressionHSC proliferationCell proliferationLogical targetCalcium signalsAdenoviral constructDownstream intracellularG2/M checkpointCaMK IIFibrosisBlockadeParvalbumin
2008
Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition
Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, Groszmann RJ, Dranoff JA, Torok NJ, Mehal WZ. Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition. Hepatology 2008, 49: 185-194. PMID: 18844235, PMCID: PMC3129263, DOI: 10.1002/hep.22589.Peer-Reviewed Original ResearchIL-6 downregulates transcription of NTPDase2 via specific promoter elements
Yu J, Lavoie E, Sheung N, Tremblay JJ, Sévigny J, Dranoff JA. IL-6 downregulates transcription of NTPDase2 via specific promoter elements. AJP Gastrointestinal And Liver Physiology 2008, 294: g748-g756. PMID: 18202114, PMCID: PMC5239663, DOI: 10.1152/ajpgi.00208.2007.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAnimalsBlotting, WesternCell DifferentiationCloning, MolecularCytokine Receptor gp130DNA, ComplementaryDown-RegulationElectrophoretic Mobility Shift AssayFibroblastsFluorescent Antibody TechniqueInterleukin-6LuciferasesMaleMicroscopy, ConfocalMutagenesis, Site-DirectedPromoter Regions, GeneticRatsRats, Sprague-DawleyResponse ElementsReverse Transcriptase Polymerase Chain ReactionConceptsBile ductular proliferationPortal fibroblastsIL-6Ductular proliferationBiliary cirrhosisIL-6 receptor gp80Alpha-smooth muscle actin expressionIL-6 responsePotential therapeutic approachMuscle actin expressionNTPDase2 expressionTime-dependent fashionBiliary fibrosisIL-6 receptor gp130Interleukin-6Therapeutic approachesResponse elementMyofibroblastic differentiationDiphosphohydrolase 2CirrhosisMRNA expressionActin expressionMinimal promoter constructProtein expressionIL-6 response element
2007
Transforming growth factor‐β and substrate stiffness regulate portal fibroblast activation in culture
Li Z, Dranoff JA, Chan EP, Uemura M, Sévigny J, Wells RG. Transforming growth factor‐β and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 2007, 46: 1246-1256. PMID: 17625791, DOI: 10.1002/hep.21792.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsPortal fibroblastsStellate cellsMyofibroblastic differentiationTGF-beta receptor kinase inhibitorGrowth factorAlpha-smooth muscle actinAlpha-smooth muscle actin expressionPlatelet-derived growth factorMuscle actin expressionReceptor kinase inhibitorBiliary fibrosisRat liver tissueFibroblast activationFibrogenic cellsMuscle actinLiver tissueMyofibroblastic phenotypeActin expressionFibroblast differentiationKinase inhibitorsDesminMyofibroblastsFibroblastsCellsSuccinate is a paracrine signal for liver damage
Correa PR, Kruglov EA, Thompson M, Leite MF, Dranoff JA, Nathanson MH. Succinate is a paracrine signal for liver damage. Journal Of Hepatology 2007, 47: 262-269. PMID: 17451837, PMCID: PMC1986575, DOI: 10.1016/j.jhep.2007.03.016.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFluorescent Antibody TechniqueIn Vitro TechniquesInfusions, IntravenousIschemiaLiverLiver DiseasesMaleParacrine CommunicationPerfusionPortal VeinPressureRatsRats, Sprague-DawleyReceptors, G-Protein-CoupledReverse Transcriptase Polymerase Chain ReactionSignal TransductionSuccinic AcidTissue DistributionConceptsHepatic stellate cellsSuccinate receptorParacrine signalsStellate cell activationStellate cellsCell expression systemTime-lapse imagingRelease of succinateCell activationCytosolic Ca2Effect of succinatePrimary hepatic stellate cellsHepatic cell typesExpression systemQuiescent hepatic stellate cellsConfocal immunofluorescencePhysiological roleIschemic hepatocytesCell typesBiochemical assaysSingle cellsLiver damageBACKGROUND/Western blotCAMP productionThe Spatial Distribution of Inositol 1,4,5-Trisphosphate Receptor Isoforms Shapes Ca2+ Waves*
Hernandez E, Leite MF, Guerra MT, Kruglov EA, Bruna-Romero O, Rodrigues MA, Gomes DA, Giordano FJ, Dranoff JA, Nathanson MH. The Spatial Distribution of Inositol 1,4,5-Trisphosphate Receptor Isoforms Shapes Ca2+ Waves*. Journal Of Biological Chemistry 2007, 282: 10057-10067. PMID: 17284437, PMCID: PMC2825872, DOI: 10.1074/jbc.m700746200.Peer-Reviewed Original ResearchMolecular basis for calcium signaling in hepatic stellate cells
Kruglov EA, Correa PR, Arora G, Yu J, Nathanson MH, Dranoff JA. Molecular basis for calcium signaling in hepatic stellate cells. AJP Gastrointestinal And Liver Physiology 2007, 292: g975-g982. PMID: 17204544, DOI: 10.1152/ajpgi.00401.2006.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusAdenosine TriphosphateAnimalsCalcium SignalingCalreticulinCell NucleusCell ShapeCell Surface ExtensionsCells, CulturedEndoplasmic ReticulumInositol 1,4,5-Trisphosphate ReceptorsLiverLiver CirrhosisMaleMicroscopy, ConfocalMicroscopy, VideoRatsRats, Sprague-DawleyReceptors, Purinergic P2RNA, MessengerTime FactorsConceptsHepatic stellate cellsCell extensionsLipid-storing cellsSubcellular organizationLiver fibrosisMolecular basisStellate cellsSubcellular signalingTrisphosphate receptorChronic liver failureProgressive liver fibrosisSufficient machineryExtracellular ATPMyofibroblastic transdifferentiationOrgan fibrosisLiver failureP2Y receptorsHealthy liverATPLocal controlCellsCritical stepLocal applicationImportant mediatorFibrosisPrevention of liver fibrosis by the purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS).
Dranoff JA, Kruglov EA, Abreu-Lanfranco O, Nguyen T, Arora G, Jain D. Prevention of liver fibrosis by the purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS). In Vivo 2007, 21: 957-65. PMID: 18210741.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsBile duct ligationLiver fibrosisDuct ligationPurinergic receptorsCommon bile duct ligationEffect of PPADSPurinergic receptor inhibitorsDevelopment of cirrhosisHSC proliferationEffective pharmacologic treatmentExperimental liver fibrosisAnnexin V flow cytometryEffect of suraminSirius red stainQuantitative RT-PCRPharmacologic treatmentReceptor inhibitorsPPADSStellate cellsLiver sectionsFibrosisBromodeoxyuridine uptakePurinoceptor activationExperimental animals
2006
Cloning, purification, and identification of the liver canalicular ecto-ATPase as NTPDase8
Fausther M, Lecka J, Kukulski F, Lévesque S, Pelletier J, Zimmermann H, Dranoff JA, Sévigny J. Cloning, purification, and identification of the liver canalicular ecto-ATPase as NTPDase8. AJP Gastrointestinal And Liver Physiology 2006, 292: g785-g795. PMID: 17095758, PMCID: PMC3952495, DOI: 10.1152/ajpgi.00293.2006.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAmino Acid SequenceAnimalsAntigens, CDApyraseCatalysisCell LineChlorocebus aethiopsCloning, MolecularCOS CellsDeoxycholic AcidEnzyme InhibitorsHepatocytesHumansKineticsLiverMolecular Sequence DataNucleotidesRatsRats, Sprague-DawleyRecombinant ProteinsSequence Homology, Amino AcidSodium AzideSubstrate SpecificityConceptsExtracellular nucleotidesSpecific transmembrane receptorsAmino acid sequenceTerminal amino acid sequenceHEK293T cellsCritical liver functionsNTPDase2/CD39L1Cell surface enzymeTransmembrane receptorsAcid sequenceHigh identityCOS-7Recombinant proteinsNTPDase8Molecular identityNucleoside salvageEcto-ATPaseAffigel BlueNTPDase3 expression
2005
Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts
Kruglov EA, Nathanson RA, Nguyen T, Dranoff JA. Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. AJP Gastrointestinal And Liver Physiology 2005, 290: g765-g771. PMID: 16282363, DOI: 10.1152/ajpgi.00308.2005.Peer-Reviewed Original ResearchConceptsBile duct epitheliumHepatic stellate cellsPortal fibroblastsMCP-1Biliary fibrosisDuct epitheliumMyofibroblastic transdifferentiationMCP-1/CCL2Fibrogenic liver cellsChemoattractant protein-1Ectonucleotidase NTPDase2PF proliferationAlpha-SMA levelsReceptor CCR2Stellate cellsParacrine fashionFunctional receptorsInduces proliferationImportant mediatorMuscle expressionFibrosisLiver cellsProtein 1Procollagen productionRecent evidencePortal Fibroblasts Regulate the Proliferation of Bile Duct Epithelia via Expression of NTPDase2*
Jhandier MN, Kruglov EA, Lavoie É, Sévigny J, Dranoff JA. Portal Fibroblasts Regulate the Proliferation of Bile Duct Epithelia via Expression of NTPDase2*. Journal Of Biological Chemistry 2005, 280: 22986-22992. PMID: 15799977, DOI: 10.1074/jbc.m412371200.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAnimalsBile DuctsBromodeoxyuridineCell ProliferationCholangiocarcinomaCholestasisCoculture TechniquesDNA, ComplementaryEpithelial CellsFibroblastsHumansLiverMaleMicroscopy, ConfocalMicroscopy, FluorescenceModels, BiologicalRatsRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionRNA, Small InterferingSignal TransductionTransfectionConceptsBile ductular proliferationExpression of NTPDase2Portal fibroblastsDuctular proliferationBile duct epitheliumNTPDase2 expressionMz-ChA-1 cellsPortal myofibroblastsP2Y receptorsDuct epitheliumBile duct-ligated ratsCell proliferationDuct-ligated ratsReal-time reverse transcription PCRQuantitative real-time reverse transcription PCRHuman cholangiocarcinoma cellsNovel co-culture modelMz-ChA-1 human cholangiocarcinoma cellsNucleotidase apyraseP2Y activationCo-culture modelObstructive cholestasisReverse transcription-PCRPathologic alterationsEpithelial proliferation
2004
Ectonucleotidase NTPDase2 Is Selectively Down-Regulated in Biliary Cirrhosis
Dranoff JA, Kruglov EA, Toure J, Braun N, Zimmermann H, Jain D, Knowles AF, Sévigny J. Ectonucleotidase NTPDase2 Is Selectively Down-Regulated in Biliary Cirrhosis. Journal Of Investigative Medicine 2004, 52: 475. PMID: 15651265, DOI: 10.1136/jim-52-07-42.Peer-Reviewed Original ResearchConceptsBile duct ligationNTPDase2 expressionPrimary biliary cirrhosisBiliary cirrhosisPortal fibroblastsReal-time polymerase chain reactionCCl4 administrationPolymerase chain reactionBiopsy specimensPortal areasExperimental ratsFibrous bandsNormal liverConfocal immunofluorescenceAlpha-smooth muscle actinExpression of NTPDase2Fibrogenic liver cellsHepatitis C cirrhosisLiver biopsy specimensFibrotic liver diseaseHuman liver biopsy specimensChain reactionNew therapeutic approachesHepatic stellate cellsCarbon tetrachloride administrationExpression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells
Dranoff JA, Ogawa M, Kruglov EA, Gaça M, Sévigny J, Robson SC, Wells RG. Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells. AJP Gastrointestinal And Liver Physiology 2004, 287: g417-g424. PMID: 14764443, PMCID: PMC5241161, DOI: 10.1152/ajpgi.00294.2003.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsActivated hepatic stellate cellsQuiescent hepatic stellate cellsP2Y receptorsExtracellular nucleotidesP2Y subtypesStellate cellsMRNA expressionRT-PCRInhibitor suraminP2Y receptor subtypesReceptor subtype expressionExpression of mediatorsExpression of receptorsFunctional P2Y receptorsRat hepatic stellate cellsReal-time RT-PCRP2Y nucleotide receptorsEctonucleotidase expressionLiver fibrosisReceptor subtypesSubtype expressionEctonucleotidase activityExtracellular UDPFibrogenic cellsAutocrine release of TGF‐β by portal fibroblasts regulates cell growth
Wells RG, Kruglov E, Dranoff JA. Autocrine release of TGF‐β by portal fibroblasts regulates cell growth. FEBS Letters 2004, 559: 107-110. PMID: 14960316, DOI: 10.1016/s0014-5793(04)00037-7.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsPortal fibroblastsBiliary fibrosisGrowth factorTGF-beta2Activated hepatic stellate cellsDerived growth factorTGF-beta receptorsFibroblast growth factorPF proliferationMyofibroblast populationStellate cellsFibrogenic cellsKey growth factorsAutocrine releaseFibrosisCell growthFibroblastsCellsPopulationFactorsTGFLiverReceptors