2023
Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients
Makinde H, Dunn JLM, Gadhvi G, Carns M, Aren K, Chung AH, Muhammad LN, Song J, Cuda CM, Dominguez S, Pandolfino JE, D'Amico J, Budinger GS, Assassi S, Frech TM, Khanna D, Shaeffer A, Perlman H, Hinchcliff M, Winter DR. Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients. Arthritis & Rheumatology 2023, 75: 595-608. PMID: 36281773, PMCID: PMC10165944, DOI: 10.1002/art.42380.Peer-Reviewed Original ResearchConceptsDiffuse cutaneous systemic sclerosisNonclassical monocytesClassical monocytesSSc patientsTranscriptional signatureSystemic sclerosisSkin diseasesCharacteristic transcriptional signaturesRNA-seq dataSSc skin diseaseWorse lung functionCutaneous systemic sclerosisEarly systemic sclerosisActivity outcome measuresDistinct transcriptional profilesTranscriptional profilingRNA sequencingTranscriptional profilesProspective registryDisease activityLung functionComplex clinical phenotypeGene expressionPeripheral bloodMinority cell populationA Novel MIP-1-Expressing Macrophage Subtype in BAL Fluid from Healthy Volunteers.
Reyfman PA, Malsin ES, Khuder B, Joshi N, Gadhvi G, Flozak AS, Carns MA, Aren K, Goldberg IA, Kim S, Alexander M, Sporn PHS, Misharin AV, Budinger GRS, Lam AP, Hinchcliff M, Gottardi CJ, Winter DR. A Novel MIP-1-Expressing Macrophage Subtype in BAL Fluid from Healthy Volunteers. American Journal Of Respiratory Cell And Molecular Biology 2023, 68: 176-185. PMID: 36174229, PMCID: PMC9986555, DOI: 10.1165/rcmb.2021-0123oc.Peer-Reviewed Original ResearchConceptsSingle-cell genomic technologiesCell typesSet of genesSingle-cell approachesSingle-cell RNASingle-cell dataSingle-cell studiesAmbient RNAGenomic technologiesMarker genesGene expressionCellular heterogeneityCellular environmentProtein 1RNAMacrophage heterogeneityGenesValuable resourceDistinct subpopulationsMacrophage subtypesHealthy volunteersLung environmentMacrophage subpopulationsMacrophage inflammatory protein-1Inflammatory protein-1
2015
Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated with Distinct Subsets of Systemic Sclerosis Patients in Three Independent Cohorts
Johnson ME, Mahoney JM, Taroni J, Sargent JL, Marmarelis E, Wu MR, Varga J, Hinchcliff ME, Whitfield ML. Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated with Distinct Subsets of Systemic Sclerosis Patients in Three Independent Cohorts. PLOS ONE 2015, 10: e0114017. PMID: 25607805, PMCID: PMC4301872, DOI: 10.1371/journal.pone.0114017.Peer-Reviewed Original ResearchConceptsNormal-like subsetsGenome-wide expression profilingSet of genesDifferential gene expressionDistinct signaling pathwaysInflammatory subsetSystemic sclerosisGene signatureIndependent cohortGene expression signaturesLipid signalingInnate immune pathwaysActive TGFβ signalingExpression profilingSystemic sclerosis patientsMolecular relationshipsGene expressionNon-lesional skinTGFβ signalingSignaling pathwaysSubsets of diseaseMolecular pathwaysMicroarray datasetsExpression signaturesEarly disease pathologySystems Level Analysis of Systemic Sclerosis Shows a Network of Immune and Profibrotic Pathways Connected with Genetic Polymorphisms
Mahoney JM, Taroni J, Martyanov V, Wood TA, Greene CS, Pioli PA, Hinchcliff ME, Whitfield ML. Systems Level Analysis of Systemic Sclerosis Shows a Network of Immune and Profibrotic Pathways Connected with Genetic Polymorphisms. PLOS Computational Biology 2015, 11: e1004005. PMID: 25569146, PMCID: PMC4288710, DOI: 10.1371/journal.pcbi.1004005.Peer-Reviewed Original ResearchConceptsGene-gene interaction networksGenetic risk lociInteraction networksGenome-wide gene expression datasetsRisk lociGene expression modulesSubset-specific genesExtracellular matrix remodelingGene expression datasetsExpression modulesSystemic sclerosisGene expressionGenetic polymorphismsIntrinsic subsetGenesSystem-level analysisExpression datasetsMatrix remodelingPolymorphic genesAntigen geneCell proliferationMultiple clinical cohortsOrgan fibrosisGene expression subsetsLociMolecular characterization of systemic sclerosis esophageal pathology identifies inflammatory and proliferative signatures
Taroni JN, Martyanov V, Huang CC, Mahoney JM, Hirano I, Shetuni B, Yang GY, Brenner D, Jung B, Wood TA, Bhattacharyya S, Almagor O, Lee J, Sirajuddin A, Varga J, Chang RW, Whitfield ML, Hinchcliff M. Molecular characterization of systemic sclerosis esophageal pathology identifies inflammatory and proliferative signatures. Arthritis Research & Therapy 2015, 17: 194. PMID: 26220546, PMCID: PMC4518531, DOI: 10.1186/s13075-015-0695-1.Peer-Reviewed Original ResearchConceptsSystemic sclerosisEsophageal biopsiesInflammatory signatureLarge inflammatory infiltratesConsecutive SSc patientsSmooth muscle atrophyAbsence of fibrosisSmooth muscle functionProliferative gene expression signatureGene expression subsetsSmooth muscle cellsEsophageal dilatationGene expression signaturesSSc patientsEsophageal fibrosisSerum autoantibodiesInflammatory infiltrateEsophageal pathologyImmune activationAutopsy studySSc pathogenesisSSc casesMolecular subsetsGene expressionMuscle atrophy
2013
Early Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-β and Regulates Fibrogenic Responses
Fang F, Shangguan AJ, Kelly K, Wei J, Gruner K, Ye B, Wang W, Bhattacharyya S, Hinchcliff ME, Tourtellotte WG, Varga J. Early Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-β and Regulates Fibrogenic Responses. American Journal Of Pathology 2013, 183: 1197-1208. PMID: 23906810, PMCID: PMC3791870, DOI: 10.1016/j.ajpath.2013.06.016.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsDisease Models, AnimalEarly Growth Response Protein 1Early Growth Response Protein 2Early Growth Response Protein 3FemaleFibroblastsFibrosisGene Expression ProfilingGene Expression RegulationHumansIntracellular SpaceMaleMiceMice, Inbred BALB CMiddle AgedScleroderma, SystemicSignal TransductionSkinSmad ProteinsTransforming Growth Factor betaConceptsEgr-3Genome-wide expression profilingSubstantial functional divergenceEarly growth response (EGR) gene familyEarly growth response 3Egr family membersFunctional divergenceGene familyFibroblast genesGrowth factorTranscription factorsExpression profilingBiological functionsGene expressionDistinct membersEgr familyEgr-1Canonical Smad3Distinct rolesEgr-2Normal skin fibroblastsTissue remodelingFibrotic gene expressionGenesFirst evidenceMolecular Signatures in Skin Associated with Clinical Improvement during Mycophenolate Treatment in Systemic Sclerosis
Hinchcliff M, Huang CC, Wood TA, Mahoney J, Martyanov V, Bhattacharyya S, Tamaki Z, Lee J, Carns M, Podlusky S, Sirajuddin A, Shah SJ, Chang RW, Lafyatis R, Varga J, Whitfield ML. Molecular Signatures in Skin Associated with Clinical Improvement during Mycophenolate Treatment in Systemic Sclerosis. Journal Of Investigative Dermatology 2013, 133: 1979-1989. PMID: 23677167, PMCID: PMC3714324, DOI: 10.1038/jid.2013.130.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBiopsyCluster AnalysisFemaleGene Expression RegulationGenetic HeterogeneityGenetic MarkersHumansImmunosuppressive AgentsMaleMiddle AgedMycophenolic AcidPredictive Value of TestsReverse Transcriptase Polymerase Chain ReactionScleroderma, SystemicSkin Physiological PhenomenaTranscriptomeYoung AdultConceptsMRSS improvementSystemic sclerosisIntrinsic subsetMycophenolate mofetil treatmentCyclophosphamide-treated patientsGene expression changesGene expression subsetsMycophenolate treatmentTreatment biopsiesClinical improvementMMF treatmentMofetil treatmentGene expression signaturesSSc patientsSerial biopsiesClinical trialsExpression changesBaseline gene expressionGene expressionSSc skinSkin AssociatedPatientsTargeted treatmentPatient biopsiesBiopsy
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
2011
Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma?
Wei J, Melichian D, Komura K, Hinchcliff M, Lam AP, Lafyatis R, Gottardi CJ, MacDougald OA, Varga J. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma? Arthritis & Rheumatism 2011, 63: 1707-1717. PMID: 21370225, PMCID: PMC3124699, DOI: 10.1002/art.30312.Peer-Reviewed Original ResearchConceptsSystemic sclerosisSubcutaneous adipose tissueTransgenic miceWnt-10bBiopsy specimensDermal fibrosisMouse modelAdipose tissueLesional skin biopsy specimensSkin biopsy specimensNovel mouse modelMesenchymal cellsSmooth muscle actin gene expressionSkin fibroblastsNovel animal modelFibrotic gene expressionWnt/β-catenin signalingSetting of fibrosisGrowth factor βΒ-catenin signalingPulmonary fibrosisSubcutaneous lipoatrophySkin fibrosisGene expressionMyofibroblast accumulation
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