2024
Targeting hypoxia and thrombospondin‐2 in diabetic wound healing
Huang Y, Xing H, Naud S, Kyriakides T. Targeting hypoxia and thrombospondin‐2 in diabetic wound healing. The FASEB Journal 2024, 38: e70091. PMID: 39383062, PMCID: PMC11486302, DOI: 10.1096/fj.202302429rrr.Peer-Reviewed Original ResearchConceptsThrombospondin-2Diabetic miceWound healingHIF-1aMatricellular protein thrombospondin-2Diabetic woundsImpaired wound healingWounds of diabetic miceDimethyloxalylglycine treatmentTargeting hypoxiaSustained hypoxiaDiabetic patientsTSP2 expressionCell dysfunctionIncreased neovascularizationDiabetic wound healingGenetic ablationDiabetic fibroblastsElevated glucoseReduced hypoxiaImprove healingImmunofluorescence analysisHIF-1a activationHypoxiaWestern blotting
2022
Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction
Xing H, Huang Y, Kunkemoeller B, Dahl P, Muraleetharan O, Malvankar N, Murrell M, Kyriakides T. Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction. Scientific Reports 2022, 12: 22474. PMID: 36577792, PMCID: PMC9797577, DOI: 10.1038/s41598-022-26337-1.Peer-Reviewed Original ResearchConceptsCell-derived matricesCell stiffnessFamily verprolin-homologous protein 2Active Rac1Thrombospondin-2Homologous protein 2Less traction forceCytoskeleton organizationExtracellular matrix productionMajor cell populationF-actinCytoskeletal disorganizationRegulatory roleProtein 2Matrix productionCritical functionsECM productionArt microscopy techniquesNew functionsCell populationsSpindle-like shapeRac1Normal fibroblastsFibroblastsWound space
2019
Elevated Thrombospondin 2 Contributes to Delayed Wound Healing in Diabetes
Kunkemoeller B, Bancroft T, Xing H, Morris AH, Luciano AK, Wu J, Fernandez-Hernando C, Kyriakides TR. Elevated Thrombospondin 2 Contributes to Delayed Wound Healing in Diabetes. Diabetes 2019, 68: 2016-2023. PMID: 31391172, PMCID: PMC6754242, DOI: 10.2337/db18-1001.Peer-Reviewed Original ResearchConceptsThrombospondin-2TSP2 expressionDiabetic control miceWound healingEffects of hyperglycemiaImpaired wound healingUnderlying pathological mechanismsDelayed Wound HealingMajor cellular sourceBlood vessel maturationGranulation tissue formationMajor complicationsDiabetic miceControl miceTreatment strategiesDiabetesPathological mechanismsDiabetic woundsAccelerated reepithelializationCellular sourceHigh glucoseHyperglycemiaMatricellular proteinExpression contributesHexosamine pathwayThrombospondin-2 regulates extracellular matrix production, LOX levels, and cross-linking via downregulation of miR-29
Calabro NE, Barrett A, Chamorro-Jorganes A, Tam S, Kristofik NJ, Xing H, Loye AM, Sessa WC, Hansen K, Kyriakides TR. Thrombospondin-2 regulates extracellular matrix production, LOX levels, and cross-linking via downregulation of miR-29. Matrix Biology 2019, 82: 71-85. PMID: 30876926, PMCID: PMC6710120, DOI: 10.1016/j.matbio.2019.03.002.Peer-Reviewed Original ResearchConceptsECM protein productionProtein productionLysyl oxidaseThrombospondin-2MiR-29Matricellular proteinQuantitative proteomics approachLevels of LOXExtracellular matrix productionProteomic approachECM proteinsMajor regulatorECM homeostasisExtracellular matrixMatrix productionProteinCollagen fibrillogenesisMiR-29 expressionFibrillar collagenImportant modulatorDependent processesLOX levelsRegulatorProductionHomeostasis
2018
Tunable Hydrogels Derived from Genetically Engineered Extracellular Matrix Accelerate Diabetic Wound Healing
Morris AH, Lee H, Xing H, Stamer DK, Tan M, Kyriakides TR. Tunable Hydrogels Derived from Genetically Engineered Extracellular Matrix Accelerate Diabetic Wound Healing. ACS Applied Materials & Interfaces 2018, 10: 41892-41901. PMID: 30424595, PMCID: PMC9996546, DOI: 10.1021/acsami.8b08920.Peer-Reviewed Original ResearchDecellularized materials derived from TSP2-KO mice promote enhanced neovascularization and integration in diabetic wounds
Morris AH, Stamer DK, Kunkemoeller B, Chang J, Xing H, Kyriakides TR. Decellularized materials derived from TSP2-KO mice promote enhanced neovascularization and integration in diabetic wounds. Biomaterials 2018, 169: 61-71. PMID: 29631168, PMCID: PMC5933884, DOI: 10.1016/j.biomaterials.2018.03.049.Peer-Reviewed Original ResearchConceptsUltimate tensile strengthECM-based materialsTensile strengthMechanical testingDecellularized materialsElastic modulusSynthetic biomaterialsIntact slabsMatrix propertiesExtracellular matrix propertiesCell-derived ECMBiologic scaffoldsElectron microscopyEngineering controlsMaterialsWtEfficient integrationEnhanced vascularizationModulusPromigratory propertiesScaffoldsPropertiesBiomaterialsEnhanced remodelingGreater cell migration
2017
Improving in vivo outcomes of decellularized vascular grafts via incorporation of a novel extracellular matrix
Kristofik NJ, Qin L, Calabro NE, Dimitrievska S, Li G, Tellides G, Niklason LE, Kyriakides TR. Improving in vivo outcomes of decellularized vascular grafts via incorporation of a novel extracellular matrix. Biomaterials 2017, 141: 63-73. PMID: 28667900, PMCID: PMC5918415, DOI: 10.1016/j.biomaterials.2017.06.025.Peer-Reviewed Original ResearchConceptsUnmodified graftsVascular graftsCoronary bypass proceduresMechanical propertiesMural cell recruitmentBypass proceduresRat aortaMMP levelsCell recruitmentDecreased failure rateGraftPlatelet studiesGraft mechanical propertiesNative vesselsShelf vascular graftsSmall-diameter vascular graftsTime pointsExtracellular matrixDiameter vascular graftsTensile strengthYoung's modulusWT cellsPresent studySuture retentionFailure rateA hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination
Bellini C, Kristofik NJ, Bersi MR, Kyriakides TR, Humphrey JD. A hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination. Journal Of The Mechanical Behavior Of Biomedical Materials 2017, 71: 397-406. PMID: 28412645, PMCID: PMC8344363, DOI: 10.1016/j.jmbbm.2017.01.045.Peer-Reviewed Original Research
2016
Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice
Kristofik N, Calabro NE, Tian W, Meng A, MacLauchlan S, Wang Y, Breuer CK, Tellides G, Niklason LE, Kyriakides TR. Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice. Blood 2016, 128: 1642-1650. PMID: 27471233, PMCID: PMC5034742, DOI: 10.1182/blood-2016-03-702845.Peer-Reviewed Original Research
2001
Altered Extracellular Matrix Remodeling and Angiogenesis in Sponge Granulomas of Thrombospondin 2-Null Mice
Kyriakides T, Zhu Y, Yang Z, Huynh G, Bornstein P. Altered Extracellular Matrix Remodeling and Angiogenesis in Sponge Granulomas of Thrombospondin 2-Null Mice. American Journal Of Pathology 2001, 159: 1255-1262. PMID: 11583953, PMCID: PMC1850515, DOI: 10.1016/s0002-9440(10)62512-6.Peer-Reviewed Original ResearchConceptsTSP2-null miceMatrix remodelingWild-type miceMatrix metalloproteinase-2Wild-type animalsExtracellular matrix remodelingModulators of angiogenesisFibrogenic responseImmunohistochemical analysisMetalloproteinase-2Minimal scarringMMP2 levelsSponge granulomaAngiogenesis inhibitorsMice displayVivo evidenceThrombospondin-2MiceGrowth factorImportant modulatorTissue invasionTSP2-nullWound healingAngiogenesisSignificant differencesThrombospondin‐2 plays a protective role in multistep carcinogenesis: a novel host anti‐tumor defense mechanism
Hawighorst T, Velasco P, Streit M, Hong Y, Kyriakides T, Brown L, Bornstein P, Detmar M. Thrombospondin‐2 plays a protective role in multistep carcinogenesis: a novel host anti‐tumor defense mechanism. The EMBO Journal 2001, 20: 2631-2640. PMID: 11387198, PMCID: PMC125494, DOI: 10.1093/emboj/20.11.2631.Peer-Reviewed Original ResearchMeSH Keywords9,10-Dimethyl-1,2-benzanthraceneAnimalsApoptosisCell Adhesion MoleculesCell DivisionDisease SusceptibilityEndothelial Growth FactorsFemaleGene Expression Regulation, NeoplasticLymphokinesMiceMice, Inbred StrainsMice, KnockoutNeovascularization, PathologicOligodeoxyribonucleotides, AntisensePapillomaPrecancerous ConditionsSkinSkin NeoplasmsThrombospondinsTime FactorsTranscription, GeneticVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsConceptsWild-type miceTSP-2 expressionThrombospondin-2Angiogenic switchTumor formationMultistep carcinogenesisVascular endothelial growth factorAnti-angiogenic factorsTSP-2-deficient miceEndothelial growth factorAngiogenesis inhibitor thrombospondin-2Endogenous angiogenesis inhibitorTumor cell apoptosisTumor differentiationMesenchymal stromaMulti-step tumorigenesisDefense mechanismsAngiogenesis inhibitorsProtective roleAngiogenesis factorsTumor angiogenesisTumor cellsGrowth factorCell apoptosisRegulation of Angiogenesis and Matrix Remodeling by Localized, Matrix-Mediated Antisense Gene Delivery
Kyriakides T, Hartzel T, Huynh G, Bornstein P. Regulation of Angiogenesis and Matrix Remodeling by Localized, Matrix-Mediated Antisense Gene Delivery. Molecular Therapy 2001, 3: 842-849. PMID: 11407897, DOI: 10.1006/mthe.2001.0336.Peer-Reviewed Original Research
2000
Thrombospondin 2, a matricellular protein with diverse functions
Bornstein P, Armstrong L, Hankenson K, Kyriakides T, Yang Z. Thrombospondin 2, a matricellular protein with diverse functions. Matrix Biology 2000, 19: 557-568. PMID: 11102746, DOI: 10.1016/s0945-053x(00)00104-9.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsExtracellular Matrix ProteinsGene Expression RegulationHumansMiceThrombospondinsTissue DistributionConceptsMatrix metalloproteinase-2TSP2-null miceThrombospondin-2Matricellular proteinConnective tissueGrowth of tumorsConnective tissue elementsFragility of skinFunctional abnormalitiesTissue injuryMetalloproteinase-2MMP2 activityBleeding defectMiceCell surface receptorsGrowth factorAdult animalsMode of actionBone growthMarked disparityTissue elementsSubdermal tissueAbnormalitiesDermal fibroblastsTissueThrombospondin 2 Modulates Collagen Fibrillogenesis and Angiogenesis
Bornstein P, Kyriakides T, Yang Z, Armstrong L, Birk D. Thrombospondin 2 Modulates Collagen Fibrillogenesis and Angiogenesis. Journal Of Investigative Dermatology Symposium Proceedings 2000, 5: 61-66. PMID: 11147677, DOI: 10.1046/j.1087-0024.2000.00005.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCollagenHumansMiceMice, KnockoutNeovascularization, PhysiologicSkinThrombospondinsConceptsVascular densityTSP2-null miceMatrix metalloproteinase-2 productionMetalloproteinase-2 productionConnective tissue abnormalitiesFlexor muscle tendonsExcisional skin woundsPolyvinyl alcohol spongesSilicone rubber discsAbnormal collagen fibrilsMuscle tendonSubcutaneous tissueNull miceTissue abnormalitiesDistinct abnormalitiesEndothelial cellsThrombospondin-2Matricellular proteinAlcohol spongesTHBS2 geneCell functionCell-matrix interactionsMiceSkin woundsMode of actionMatricellular Proteins as Modulators of Cell–Matrix Interactions: Adhesive Defect in Thrombospondin 2-null Fibroblasts is a Consequence of Increased Levels of Matrix Metalloproteinase-2
Yang Z, Kyriakides T, Bornstein P. Matricellular Proteins as Modulators of Cell–Matrix Interactions: Adhesive Defect in Thrombospondin 2-null Fibroblasts is a Consequence of Increased Levels of Matrix Metalloproteinase-2. Molecular Biology Of The Cell 2000, 11: 3353-3364. PMID: 11029041, PMCID: PMC14997, DOI: 10.1091/mbc.11.10.3353.Peer-Reviewed Original ResearchConceptsCell-matrix interactionsAbnormal cell-matrix interactionsWild-type cellsTSP2-null miceAdhesive defectsComplex phenotypesCell spreadingMolecular mechanismsMutant fibroblastsProtein resultsMatrix proteinsStable transfectionMatrix metalloproteinasesMetalloproteinase-2Matricellular proteinAltered expressionTHBS2 geneNull miceAffinity chromatographyGelatinolytic assaysThrombospondin-2TSP2Matrix metalloproteinase-2FibroblastsLevels of MMP2Increased Marrow‐Derived Osteoprogenitor Cells and Endosteal Bone Formation in Mice Lacking Thrombospondin 2*
Hankenson K, Bain S, Kyriakides T, Smith E, Goldstein S, Bornstein P. Increased Marrow‐Derived Osteoprogenitor Cells and Endosteal Bone Formation in Mice Lacking Thrombospondin 2*. Journal Of Bone And Mineral Research 2000, 15: 851-862. PMID: 10804014, DOI: 10.1359/jbmr.2000.15.5.851.Peer-Reviewed Original ResearchConceptsBone formation rateEndosteal bone formation rateEndosteal bone formationTSP2-null miceMarrow stromal cellsComputerized tomographyThrombospondin-2Bone formationNormal bone resorptionWild-type animalsOvariectomized miceBone lossCortical densityRate of proliferationBone resorptionLigamentous laxityBone massVascular densityHistomorphometric analysisNull miceMutant miceStromal cellsMiceLong bonesCellular basis
1999
Accelerated Wound Healing in Mice With a Disruption of the Thrombospondin 2 Gene
Kyriakides T, Tam J, Bornstein P. Accelerated Wound Healing in Mice With a Disruption of the Thrombospondin 2 Gene. Journal Of Investigative Dermatology 1999, 113: 782-787. PMID: 10571734, DOI: 10.1046/j.1523-1747.1999.00755.x.Peer-Reviewed Original ResearchConceptsGranulation tissueThrombospondin-2Late woundsControl woundsWound healingExtent of angiogenesisRe-epithelization rateAbnormal collagen fibrilsVascular densityLess scarringRete pegsHistologic analysisExcisional woundsControl epitheliumSuch woundsThrombospondin 2 geneTotal cellular contentAccelerated wound healingElevated levelsHealing processMiceWoundsBiopsy punchEarly woundsHealingMice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity
Kyriakides T, Leach K, Hoffman A, Ratner B, Bornstein P. Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 4449-4454. PMID: 10200282, PMCID: PMC16352, DOI: 10.1073/pnas.96.8.4449.Peer-Reviewed Original Research
1998
The Distribution of the Matricellular Protein Thrombospondin 2 in Tissues of Embryonic and Adult Mice
Kyriakides T, Zhu Y, Yang Z, Bornstein P. The Distribution of the Matricellular Protein Thrombospondin 2 in Tissues of Embryonic and Adult Mice. Journal Of Histochemistry & Cytochemistry 1998, 46: 1007-1015. PMID: 9705966, DOI: 10.1177/002215549804600904.Peer-Reviewed Original ResearchConceptsCell-matrix interactionsMatricellular protein thrombospondin-2Adult tissuesThrombospondin-2TSP2-null micePleiotropic phenotypesTissue-forming cellsCell movementEmbryonic developmentDermal fibroblastsPericellular environmentAdhesion defectsDay 15Connective tissueLeidig cellsTissue repairDay 18 embryosDermal cellsCellsMice That Lack Thrombospondin 2 Display Connective Tissue Abnormalities That Are Associated with Disordered Collagen Fibrillogenesis, an Increased Vascular Density, and a Bleeding Diathesis
Kyriakides T, Zhu Y, Smith L, Bain S, Yang Z, Lin M, Danielson K, Iozzo R, LaMarca M, McKinney C, Ginns E, Bornstein P. Mice That Lack Thrombospondin 2 Display Connective Tissue Abnormalities That Are Associated with Disordered Collagen Fibrillogenesis, an Increased Vascular Density, and a Bleeding Diathesis. Journal Of Cell Biology 1998, 140: 419-430. PMID: 9442117, PMCID: PMC2132586, DOI: 10.1083/jcb.140.2.419.Peer-Reviewed Original ResearchConceptsTSP2-null miceEmbryonic stem cellsCollagen fibrillogenesisGenetic disorder resultsCell surface propertiesHomologous recombinationExtracellular proteinsMutant animalsBlastocyst injectionAppropriate breedingStructural roleMendelian frequencyMouse tissuesMesenchymal cellsStem cellsUnusual phenotypeCell functionMutant miceThrombospondin-2TSP2Von Willebrand factorSkin fibroblastsConnective tissue abnormalitiesLarge fibrilsWillebrand factor