2024
Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Ruz-Maldonado I, Gonzalez J, Zhang H, Sun J, Bort A, Kabir I, Kibbey R, Suárez Y, Greif D, Fernández-Hernando C. Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage. Nature Communications 2024, 15: 1247. PMID: 38341404, PMCID: PMC10858916, DOI: 10.1038/s41467-024-45439-0.Peer-Reviewed Original Research
2023
The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques
Kabir I, Zhang X, Dave J, Chakraborty R, Qu R, Chandran R, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin K, Fernández-Hernando C, Greif D. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques. Nature Aging 2023, 3: 64-81. PMID: 36743663, PMCID: PMC9894379, DOI: 10.1038/s43587-022-00342-5.Peer-Reviewed Original ResearchConceptsAtherosclerotic plaquesBone marrowSmooth muscle-derived cellsSMC progenitorsAtherosclerotic plaque cellsSmooth muscle cell progenitorsPredominant risk factorCause of deathNovel therapeutic strategiesTNF receptor 1Muscle-derived cellsAged bone marrowAged BMEffect of agePlaque burdenAged miceRisk factorsTumor necrosisTherapeutic strategiesPlaque cellsMyeloid cellsReceptor 1Integrin β3Cell progenitorsAtherosclerosis
2022
Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity
Chakraborty R, Ostriker AC, Xie Y, Dave JM, Gamez-Mendez A, Chatterjee P, Abu Y, Valentine J, Lezon-Geyda K, Greif DM, Schulz VP, Gallagher PG, Sessa WC, Hwa J, Martin KA. Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity. Circulation 2022, 145: 1720-1737. PMID: 35502657, DOI: 10.1161/circulationaha.121.057599.Peer-Reviewed Original ResearchConceptsHistone acetylationContractile genesContractile protein expressionPhenotypic switchingHistone acetyl transferase p300Human intimal hyperplasiaPlatelet-derived growth factor treatmentAcetyl transferase p300Key regulatory mechanismSmooth muscle cell phenotypeP300 expressionP300-dependent acetylationSmooth muscle plasticityDistinct functional interactionsMuscle cell phenotypeProtein expressionIntimal hyperplasiaRole of p300Methylcytosine dioxygenase TET2Chromatin modificationsEpigenetic regulationVSMC phenotypic switchingSpecific histoneCardiovascular diseaseMaster regulatorJAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency
Dave JM, Chakraborty R, Ntokou A, Saito J, Saddouk FZ, Feng Z, Misra A, Tellides G, Riemer RK, Urban Z, Kinnear C, Ellis J, Mital S, Mecham R, Martin KA, Greif DM. JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency. Journal Of Clinical Investigation 2022, 132: e142338. PMID: 34990407, PMCID: PMC8884911, DOI: 10.1172/jci142338.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsSupravalvular aortic stenosisEndothelial cellsElastin insufficiencyObstructive arterial diseaseAortic smooth muscle cellsΓ-secretaseAortic vascular cellsPotential therapeutic targetNotch3 intracellular domainNotch ligand Jagged1Aortic stenosisArterial diseasePathological featuresPharmacological treatmentJag1 deletionLuminal obstructionMouse modelNotch3 activationTherapeutic targetSMC accumulationPathway upregulationAortic samplesMice displayNotch3 deletion
2021
Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
Chandran RR, Xie Y, Gallardo-Vara E, Adams T, Garcia-Milian R, Kabir I, Sheikh AQ, Kaminski N, Martin KA, Herzog EL, Greif DM. Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis. Nature Communications 2021, 12: 7179. PMID: 34893592, PMCID: PMC8664937, DOI: 10.1038/s41467-021-27499-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationDisease Models, AnimalDown-RegulationExtracellular MatrixFemaleFibroblastsFibrosisHumansKruppel-Like Factor 4LungLung InjuryMaleMesenchymal Stem CellsMiceMice, Inbred C57BLMyofibroblastsReceptor, Platelet-Derived Growth Factor betaRespiratory Tract DiseasesSignal TransductionTransforming Growth Factor betaConceptsMesenchymal cell typesPlatelet-derived growth factor receptorSmooth muscle actinLung fibrosisKruppel-like factor 4Forkhead box M1Growth factor receptorCell transitionCell typesExtracellular matrixDistinct rolesKLF4Box M1C chemokine ligandMesenchymal cell subtypesFactor receptorPro-fibrotic effectsFactor 4PDGFRMesenchymeCellsMacrophage accumulationKLF4 levelsChemokine ligandLung fibrogenesisMacrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension
Ntokou A, Dave JM, Kauffman AC, Sauler M, Ryu C, Hwa J, Herzog EL, Singh I, Saltzman WM, Greif DM. Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension. JCI Insight 2021, 6: e139067. PMID: 33591958, PMCID: PMC8026182, DOI: 10.1172/jci.insight.139067.Peer-Reviewed Original ResearchConceptsRight ventricle hypertrophyPulmonary hypertensionDistal muscularizationSmooth muscle cellsHypoxia-inducible factor 2APulmonary arterial hypertension patientsLysM-Cre miceArterial hypertension patientsHuman pulmonary hypertensionHypoxia-inducible factor 1aPlatelet-derived growth factorMacrophage-conditioned mediumVentricle hypertrophyHypertension patientsDistal arteriolesMacrophage accumulationFl miceCardiovascular diseaseInterventional strategiesMuscularizationHypoxia exposureExcess macrophagesSMC proliferationLethal diseaseMuscle cellsMacrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis
Gao R, Peng X, Perry C, Sun H, Ntokou A, Ryu C, Gomez JL, Reeves BC, Walia A, Kaminski N, Neumark N, Ishikawa G, Black KE, Hariri LP, Moore MW, Gulati M, Homer RJ, Greif DM, Eltzschig HK, Herzog EL. Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis. Journal Of Clinical Investigation 2021, 131: e136542. PMID: 33393489, PMCID: PMC7773383, DOI: 10.1172/jci136542.Peer-Reviewed Original ResearchConceptsNetrin-1Lung fibrosisCell-specific knockout miceΑ1-adrenoreceptor blockadeIPF lung tissueNeuronal guidance proteinsNetrin-1 expressionExtracellular matrix accumulationAdrenergic processesAdrenoreceptor antagonismAdrenoreceptor blockadeFibrotic histologyInflammatory scarringIPF cohortAdrenergic nervesΑ1-blockersImproved survivalColorectal carcinomaLung tissueKnockout miceCollagen accumulationFibrosisMatrix accumulationMacrophagesGuidance proteins
2019
Promoters to Study Vascular Smooth Muscle
Chakraborty R, Saddouk FZ, Carrao AC, Krause DS, Greif DM, Martin KA. Promoters to Study Vascular Smooth Muscle. Arteriosclerosis Thrombosis And Vascular Biology 2019, 39: 603-612. PMID: 30727757, PMCID: PMC6527360, DOI: 10.1161/atvbaha.119.312449.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell LineCell LineageCell TransdifferentiationGene Expression RegulationGene Knockout TechniquesGene TargetingHumansMiceMicrofilament ProteinsMuscle ProteinsMuscle, Smooth, VascularMyocytes, Smooth MuscleMyofibroblastsMyosin Heavy ChainsNeovascularization, PathologicNeovascularization, PhysiologicPhenotypePromoter Regions, GeneticRecombinant Fusion ProteinsConceptsSmooth muscle cellsCre driver linesDiversity of phenotypesMuscle cell typesVisceral smooth muscle cellsSMC transdifferentiationActa2 promoterRemarkable plasticityExciting new eraSMC functionCell typesCre linesEmbryonic heartExciting discoveriesPhenotypeMuscle cellsPerivascular adipocytesPromoterVascular smooth muscleNonmuscular cellsExpressionMyeloid cellsCardiovascular phenotypesCellsBlood vessel wall
2018
NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy
Dubrac A, Künzel SE, Künzel SH, Li J, Chandran RR, Martin K, Greif DM, Adams RH, Eichmann A. NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy. Nature Communications 2018, 9: 3463. PMID: 30150707, PMCID: PMC6110853, DOI: 10.1038/s41467-018-05926-7.Peer-Reviewed Original ResearchConceptsNeovascular tuftsPericyte migrationMural cellsPathological neovascular tuftsPDGF-B overexpressionTreatment of retinopathyOxygen-induced retinopathyCapillary barrier functionΑ-SMA expressionPlatelet-derived growth factor receptorPlatelet-derived growth factorPhosphorylation of PDGFRβGrowth factor receptorIschemic retinopathyProliferative retinopathyEndothelial-specific knockoutVascular leakagePericyte depletionPathological neovascularizationGenetic lineage tracingMouse modelPericyte proliferationNck2 adaptor proteinRetinopathyBarrier functionIntegrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells
Misra A, Feng Z, Chandran RR, Kabir I, Rotllan N, Aryal B, Sheikh AQ, Ding L, Qin L, Fernández-Hernando C, Tellides G, Greif DM. Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nature Communications 2018, 9: 2073. PMID: 29802249, PMCID: PMC5970166, DOI: 10.1038/s41467-018-04447-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAtherosclerosisBone Marrow TransplantationCell MovementCell ProliferationCell TransdifferentiationCells, CulturedCholesterolDisease Models, AnimalFemaleHumansIntegrin beta3MacrophagesMaleMiceMice, Inbred C57BLMice, Knockout, ApoEMuscle, Smooth, VascularMyocytes, Smooth MusclePlaque, AtheroscleroticConceptsSmooth muscle cellsPre-existing smooth muscle cellsAtherosclerotic plaquesPlaque cellsToll-like receptor 4 expressionSmooth muscle-derived cellsBone marrow-derived cellsSingle smooth muscle cellsAtherosclerotic plaque cellsReceptor 4 expressionMarrow-derived cellsBone marrow resultsMuscle-derived cellsIntegrin β3 levelsMacrophage-like phenotypeCD36 levelsMarrow resultsSMC proliferationPlaque coresSMC progenitorsMuscle cellsIntegrin β3AtherogenesisPlaquesIntegrin beta3Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension
Sheikh AQ, Saddouk FZ, Ntokou A, Mazurek R, Greif DM. Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension. Cell Reports 2018, 23: 1152-1165. PMID: 29694892, PMCID: PMC5959296, DOI: 10.1016/j.celrep.2018.03.043.Peer-Reviewed Original ResearchConceptsPulmonary hypertensionMyeloid cellsPlatelet-derived growth factor receptor βGrowth factor receptor βKruppel-like factor 4Muscle cell markersAttractive therapeutic targetHypoxia-inducible factor-1Vascular muscularizationDistal migrationNormal lungSmall arteriolesMuscle expansionHypertensionTherapeutic targetNon-cell autonomous pathwaysReceptor βCell expressionCell inductionCell markersSMC progenitorsEndothelial cellsFactor 1Factor 4MuscularizationPericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain
Dave JM, Mirabella T, Weatherbee SD, Greif DM. Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Developmental Cell 2018, 44: 665-678.e6. PMID: 29456135, PMCID: PMC5871595, DOI: 10.1016/j.devcel.2018.01.018.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood-Brain BarrierBrainEmbryo, MammalianEndothelium, VascularFemaleHumansIntracranial HemorrhagesMaleMiceMice, Inbred C57BLMice, KnockoutMorphogenesisPericytesProtein Serine-Threonine KinasesReceptor, Transforming Growth Factor-beta Type IReceptors, Transforming Growth Factor betaSignal TransductionTissue Inhibitor of Metalloproteinase-3ConceptsEndothelial morphogenesisReceptor-like kinasesBlood-brain barrierActivin receptor-like kinaseGerminal matrixGerminal matrix hemorrhage-intraventricular hemorrhageMurine embryosEC morphogenesisEndothelial cellsEC hyperproliferationMorphogenesisMatrix metalloproteinase-3Glial precursorsBasement membrane collagenMatrix metalloproteinase activityBBB developmentMutantsVascular stabilityALK5Brain pericytesAbnormal dilationSubstantial therapeutic potentialMetalloproteinase-3Membrane collagenTissue inhibitor
2017
Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta.
Misra A, Feng Z, Zhang J, Lou ZY, Greif DM. Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta. Journal Of Visualized Experiments 2017 PMID: 28930997, PMCID: PMC5752224, DOI: 10.3791/56039.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsAortic smooth muscle cellsPregnant micePharmacological agentsAortic wallAortaLarge arteriesAdult aortaMuscle cellsEndothelial cellsPathological modelsHypothesis-generating experimentsContinuous exposureCell explantsTissue explantsPathogenesisFate mappingSpecific gene targetsClonal analysisNormal developmentVivoGene targetsExtracellular matrixClonal architectureCellsmTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice
Jiao Y, Li G, Li Q, Ali R, Qin L, Li W, Qyang Y, Greif DM, Geirsson A, Humphrey JD, Tellides G. mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice. Arteriosclerosis Thrombosis And Vascular Biology 2017, 37: 1657-1666. PMID: 28751568, PMCID: PMC5574180, DOI: 10.1161/atvbaha.117.309653.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAorta, ThoracicAortic DiseasesCell ProliferationCollagenElastinEverolimusFocal Adhesion Kinase 1Genetic Predisposition to DiseaseHumansImatinib MesylateMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2Mechanotransduction, CellularMice, Inbred C57BLMice, KnockoutMultiprotein ComplexesMuscle, Smooth, VascularPhenotypePhosphorylationProtein Kinase InhibitorsSirolimusTime FactorsTOR Serine-Threonine KinasesVascular StiffnessWilliams SyndromeConceptsElastin deficiencyCollagen accumulationArterial phenotypeNull miceGrowth factorSmooth muscle cell proliferationMuscle cell proliferationEarly postnatal deathInhibition of mTORAortic fibrosisAortic obstructionMedial thickeningAortic stiffeningNeonatal deathLuminal stenosisPharmacological blockadeAbsence of elastinThoracic aortaTherapeutic benefitJuvenile micePostnatal deathMTOR inhibitionAortaHeterozygous lossMice
2016
Chapter Eight Vascular Cells in Blood Vessel Wall Development and Disease
Mazurek R, Dave JM, Chandran RR, Misra A, Sheikh AQ, Greif DM. Chapter Eight Vascular Cells in Blood Vessel Wall Development and Disease. Advances In Pharmacology 2016, 78: 323-350. PMID: 28212800, PMCID: PMC5559712, DOI: 10.1016/bs.apha.2016.08.001.BooksConceptsDistinct cellular layersVascular cellsRegulated processGenetic approachesWall developmentDevelopmental eventsIndividual cellsDiverse vascular diseasesCellular mechanismsCell proliferationCellsNormal vascular wallCellular layersMorphogenesisTherapeutic strategiesBiologyDifferentiationVascular wallMajor ramificationsProliferationFurther investigationVessel wallMigrationIntegrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis
Misra A, Sheikh AQ, Kumar A, Luo J, Zhang J, Hinton RB, Smoot L, Kaplan P, Urban Z, Qyang Y, Tellides G, Greif DM. Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis. Journal Of Experimental Medicine 2016, 213: 451-463. PMID: 26858344, PMCID: PMC4813675, DOI: 10.1084/jem.20150688.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsMutant miceTherapeutic strategiesAortic stenosis patientsAortic smooth muscle cellsSupravalvular aortic stenosisAttractive therapeutic strategyIntegrin β3 levelsAortic pathologyAortic stenosisStenosis patientsArterial diseaseLumen lossPathological featuresArterial mediaLarge arteriesAortic mediaElastin deficiencyPharmacological inhibitionMuscle cellsStenosisMicePathological stenosisExplant culturesSVAS patients
2015
Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension
Sheikh AQ, Misra A, Rosas IO, Adams RH, Greif DM. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension. Science Translational Medicine 2015, 7: 308ra159. PMID: 26446956, PMCID: PMC4629985, DOI: 10.1126/scitranslmed.aaa9712.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsKruppel-like factor 4Pulmonary hypertensionSmooth muscleHypoxia-induced pulmonary hypertensionPathogenesis of PHPulmonary artery blood pressureSMC progenitorsArteriole smooth muscleArtery blood pressureSmooth muscle cell progenitorsCardiovascular disease pathogenesisPlatelet-derived growth factor receptorHypoxia-induced expressionGrowth factor receptorPH patientsBlood pressurePulmonary arteriolesVascular disordersTherapeutic strategiesDisease pathogenesisKLF4 levelsKLF4 expressionDistal extensionMuscle cells
2014
Brain vessels squeezed to death
Greif DM, Eichmann A. Brain vessels squeezed to death. Nature 2014, 508: 50-51. PMID: 24670635, DOI: 10.1038/nature13217.Commentaries, Editorials and LettersRecapitulation of Developing Artery Muscularization in Pulmonary Hypertension
Sheikh AQ, Lighthouse JK, Greif DM. Recapitulation of Developing Artery Muscularization in Pulmonary Hypertension. Cell Reports 2014, 6: 809-817. PMID: 24582963, PMCID: PMC4015349, DOI: 10.1016/j.celrep.2014.01.042.Peer-Reviewed Original ResearchConceptsPulmonary artery hypertensionArtery hypertensionArteriole smooth muscle cellsSmooth muscle accumulationPulmonary artery complianceModest clinical benefitStrong independent predictorMuscle cell dedifferentiationSmooth muscle cellsPulmonary hypertensionArtery complianceIndependent predictorsClinical benefitPulmonary vasculatureDistal migrationVascular disordersAlveolar myofibroblastsSmooth muscleHypertensionMuscle accumulationMuscularizationMuscle cellsCell dedifferentiationPoor understandingAtherosclerosis
2013
Development and pathologies of the arterial wall
Seidelmann SB, Lighthouse JK, Greif DM. Development and pathologies of the arterial wall. Cellular And Molecular Life Sciences 2013, 71: 1977-1999. PMID: 24071897, PMCID: PMC11113178, DOI: 10.1007/s00018-013-1478-y.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenic ProteinsAnimalsArteriesCardiovascular DiseasesCell DifferentiationCell LineageEndothelial CellsEndothelium, VascularGene Expression Regulation, DevelopmentalHumansMorphogenesisMuscle, Smooth, VascularMyocytes, Smooth MuscleNeovascularization, PathologicNeovascularization, PhysiologicConceptsAdventitial progenitor cellsDevastating vascular diseaseDevelopmental biologyWall developmentSmooth muscle cell originHuman diseasesExtracellular matrixMuscle cell originProcess of angiogenesisProgenitor cellsEndothelial networksDisease mechanismsNovel therapeutic strategiesDevelopmental studiesEndothelial cellsSmooth muscleCellsMorphogenesisTherapeutic strategiesCell originBiologyDifferentiationVascular diseaseVascular wallVascular wall abnormalities