2022
Human dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis
Bhandari R, Yang H, Kosarek NN, Smith AE, Garlick JA, Hinchcliff M, Whitfield ML, Pioli PA. Human dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis. Rheumatology 2022, 62: si114-si124. PMID: 35946522, PMCID: PMC9910573, DOI: 10.1093/rheumatology/keac453.Peer-Reviewed Original ResearchMeSH KeywordsCells, CulturedExosomesFibroblastsFibrosisHumansInflammationMacrophage ActivationScleroderma, SystemicSkinConceptsFibroblast-derived exosomesSSc patientsMacrophage activationGender-matched control subjectsSSc fibroblastsDonor-derived macrophagesReciprocal activationUpregulated surface expressionMHC class IICo-cultured macrophagesHealthy control fibroblastsExtracellular matrix depositionCell typesSystemic sclerosisHealthy ageIL-10Production of collagenIL-12p40IL-6Control subjectsSkin biopsiesSSc skinTherapeutic targetingClass IIFlow cytometry
2019
Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis
Reyfman PA, Walter JM, Joshi N, Anekalla KR, McQuattie-Pimentel AC, Chiu S, Fernandez R, Akbarpour M, Chen CI, Ren Z, Verma R, Abdala-Valencia H, Nam K, Chi M, Han S, Gonzalez-Gonzalez FJ, Soberanes S, Watanabe S, Williams KJN, Flozak AS, Nicholson TT, Morgan VK, Winter DR, Hinchcliff M, Hrusch CL, Guzy RD, Bonham CA, Sperling AI, Bag R, Hamanaka RB, Mutlu GM, Yeldandi AV, Marshall SA, Shilatifard A, Amaral LAN, Perlman H, Sznajder JI, Argento AC, Gillespie CT, Dematte J, Jain M, Singer BD, Ridge KM, Lam AP, Bharat A, Bhorade SM, Gottardi CJ, Budinger GRS, Misharin AV. Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2019, 199: 1517-1536. PMID: 30554520, PMCID: PMC6580683, DOI: 10.1164/rccm.201712-2410oc.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingRNA sequencingPulmonary fibrosisAlveolar macrophagesLung tissueSingle-cell transcriptomic analysisEpithelial cellsCell populationsNext-generation sequencing technologiesSingle-cell atlasHuman lungDiverse cell populationsExpression of genesRare cell populationsPulmonary fibrosis pathogenesisIdiopathic pulmonary fibrosisAirway stem cellsIndividual cell populationsTranscriptomic analysisSequencing technologiesWnt secretionRNA hybridizationSenescent cellsTransplant donorsDiscovery-based approach
2016
Tenascin-C drives persistence of organ fibrosis
Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, Lafyatis R, Lee J, Hinchcliff M, Feghali-Bostwick C, Lakota K, Budinger GR, Raparia K, Tamaki Z, Varga J. Tenascin-C drives persistence of organ fibrosis. Nature Communications 2016, 7: 11703. PMID: 27256716, PMCID: PMC4895803, DOI: 10.1038/ncomms11703.Peer-Reviewed Original ResearchConceptsSystemic sclerosisToll-like receptorsOrgan fibrosisFibrosis resolutionPathogenesis of SScTreatment of SScLevels of tenascinEndogenous danger signalsSSc skin biopsy samplesSkin biopsy samplesMechanism of actionLung fibrosisPathogenic roleTLR activatorsMouse modelBiopsy samplesFibroblast activationDanger signalsMyofibroblast transformationFibrosisSSc fibroblastsCollagen gene expressionSkin fibroblastsAmplification loopTenascin
2015
The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling
Wei J, Ghosh AK, Chu H, Fang F, Hinchcliff ME, Wang J, Marangoni RG, Varga J. The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling. Arthritis & Rheumatology 2015, 67: 1323-1334. PMID: 25707573, PMCID: PMC4518870, DOI: 10.1002/art.39061.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCase-Control StudiesCells, CulturedDisease Models, AnimalEnzyme InhibitorsFibroblastsHumansMiceP300-CBP Transcription FactorsPlatelet-Derived Growth FactorReal-Time Polymerase Chain ReactionResveratrolRNA, MessengerScleroderma, SystemicSignal TransductionSirtuin 1SkinSmad ProteinsStilbenesTransforming Growth Factor betaConceptsGenome-wide expression data setsTransforming Growth Factor β SignalingGrowth factor β signalingSSc skin biopsy samplesSirtuin 1Histone deacetylase sirtuin 1Tissue expressionExpression data setsPlatelet-derived growth factorTranscriptome dataDeacetylase sirtuin 1Epigenetic mechanismsAcetyltransferase p300Acetylation statusEnzyme sirtuin 1Persistent fibroblast activationEffect of SIRT1Β signalingMessenger RNA levelsMouse fibroblastsFibrotic responseLoss of SIRT1Activation of SIRT1Pharmacologic inhibitionExperimental fibrosis model
2013
A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses
Wei J, Zhu H, Komura K, Lord G, Tomcik M, Wang W, Doniparthi S, Tamaki Z, Hinchcliff M, Distler JH, Varga J. A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses. Annals Of The Rheumatic Diseases 2013, 73: 446. PMID: 23515440, PMCID: PMC4028127, DOI: 10.1136/annrheumdis-2012-202716.Peer-Reviewed Original ResearchMeSH KeywordsAdipogenesisAdultAnimalsBiopsyCells, CulturedCollagenDisease Models, AnimalDrug Evaluation, PreclinicalFemaleFibroblastsFibrosisHumansInfant, NewbornMiceMice, Inbred C57BLOleanolic AcidOrgan Culture TechniquesPPAR gammaProto-Oncogene Proteins c-aktScleroderma, SystemicSignal TransductionSkinTransforming Growth Factor betaConceptsSkin organ cultureHuman skin organ cultureAntifibrotic effectsDermal fibrosisExperimental fibrosisOrgan culturePeroxisome proliferator-activated receptor γModulation of fibrogenesisProliferator-activated receptor γHuman skin equivalentsPotential new therapiesPotential therapeutic strategyFibrotic gene expressionSynthetic oleanane triterpenoidComplementary mouse modelsControl of fibrosisPersistent fibroblast activationGrowth factor βTGF-β signalingEffects of CDDOSystemic sclerosisBleomycin injectionFibrogenic responseFibrotic activityMurine model
2012
Wnt/β‐catenin signaling is hyperactivated in systemic sclerosis and induces Smad‐dependent fibrotic responses in mesenchymal cells
Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, Gottardi CJ, Atit R, Whitfield ML, Varga J. Wnt/β‐catenin signaling is hyperactivated in systemic sclerosis and induces Smad‐dependent fibrotic responses in mesenchymal cells. Arthritis & Rheumatism 2012, 64: 2734-2745. PMID: 22328118, PMCID: PMC3553791, DOI: 10.1002/art.34424.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdultBeta CateninBiopsyCase-Control StudiesCell MovementCell ProliferationCells, CulturedFibroblastsFibrosisFrizzled ReceptorsHumansIntercellular Signaling Peptides and ProteinsLymphoid Enhancer-Binding Factor 1MesodermRepressor ProteinsScleroderma, SystemicSignal TransductionSkinSmad ProteinsWnt ProteinsWnt3A ProteinConceptsWnt/β-cateninCanonical WntWnt-3aMesenchymal cellsGenome-wide expression dataAberrant Wnt/β-catenin pathway activationCell fate specificationΒ-cateninSkin biopsy specimensMyofibroblast differentiationCanonical Wnt/β-cateninWnt/β-catenin signalingWnt receptor Fzd2Subcutaneous preadipocytesSystemic sclerosisΒ-catenin signalingFate specificationBiopsy specimensΒ-catenin activationExpression of WntHuman mesenchymal cellsGrowth factor βPathway componentsGene expressionProfibrotic responsesImatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro.
Hinchcliff M, Huang CC, Ishida W, Fang F, Lee J, Jafari N, Wilkes M, Bhattacharyya S, Leof E, Varga J. Imatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro. Clinical And Experimental Rheumatology 2012, 30: s86-96. PMID: 22691216, PMCID: PMC3860597.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBiopsyCase-Control StudiesCells, CulturedFibroblastsFibrosisGene Expression ProfilingGene Expression RegulationHumansImatinib MesylateMiceMice, KnockoutOligonucleotide Array Sequence AnalysisPhosphorylationPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-ablPyrimidinesScleroderma, SystemicSignal TransductionSkinTime FactorsTranscription, GeneticTransforming Growth Factor beta1ConceptsSystemic sclerosisSSc fibroblastsSkin biopsiesInternal organ fibrosisHeterogeneous multifactorial diseaseControl fibroblastsControl skin biopsiesFibrotic gene expressionSystemic sclerosis fibroblastsC-AblProgressive skinAntifibrotic effectsImatinib mesylateHealthy controlsCardiovascular diseaseGene expressionHealthy subjectsFibrotic responseCholesterol metabolismOrgan fibrosisC-Abl activationMultifactorial diseaseTreatment resultsTissue levelsFibrosis
2009
A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate
Bhattacharyya S, Ishida W, Wu M, Wilkes M, Mori Y, Hinchcliff M, Leof E, Varga J. A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate. Oncogene 2009, 28: 1285-1297. PMID: 19151753, PMCID: PMC4006376, DOI: 10.1038/onc.2008.479.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBleomycinCells, CulturedCollagenEarly Growth Response Protein 1Extracellular Signal-Regulated MAP KinasesFibroblastsFibrosisHumansImatinib MesylateMiceMice, Inbred BALB CNIH 3T3 CellsPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-ablPyrimidinesSignal TransductionSmad2 ProteinSmad3 ProteinTransforming Growth Factor betaConceptsChronic myelogenous leukemiaFibrotic responseEgr-1Growth factorUpregulated tissue expressionFibrosis of skinNovel therapeutic approachesEarly growth response factor-1Kinase-deficient mutant formC-AblNormal fibroblastsTGF-β stimulationIntracellular signaling mechanismLesional skinStimulation of collagenImatinib mesylateMouse embryonic fibroblastsFibrotic processMyelogenous leukemiaTherapeutic approachesPharmacological targetingTarget of inhibitionTGF-β responseFibroblast activationC-Abl activation
2007
Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-β responsiveness
Mori Y, Hinchcliff M, Wu M, Warner-Blankenship M, Lyons K, Varga J. Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-β responsiveness. Experimental Cell Research 2007, 314: 1094-1104. PMID: 18201696, PMCID: PMC3963386, DOI: 10.1016/j.yexcr.2007.12.010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell ProliferationCells, CulturedCollagenCollagen Type IConnective Tissue Growth FactorEmbryo, MammalianExtracellular MatrixFibroblastsFibrosisGene ExpressionImmediate-Early ProteinsIntercellular Signaling Peptides and ProteinsMiceSignal TransductionSmad ProteinsTransforming Growth Factor betaConceptsEmbryonic fibroblastsSmad-dependent transcriptional responsesTGF-beta signal transductionMatricellular protein connective tissue growth factorMurine embryonic fibroblastsMouse embryonic fibroblastsProtein connective tissue growth factorWild-type MEFsTransient transfection assaysMyofibroblast transdifferentiationCCN2 expressionRegulation of proliferationCorresponding protein levelsCCN2 functionsCollagen gene expressionTranscriptional responseRT-PCR analysisLoss of CCN2Signal transductionEndogenous CCN2Transfection assaysExtracellular matrix synthesisMouse embryosGene expressionWild type