2023
Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis
Ozmen A, Nwabuobi C, Tang Z, Guo X, Larsen K, Guller S, Blas J, Moore M, Kayisli U, Lockwood C, Guzeloglu-Kayisli O. Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis. International Journal Of Molecular Sciences 2023, 25: 135. PMID: 38203306, PMCID: PMC10778808, DOI: 10.3390/ijms25010135.Peer-Reviewed Original ResearchConceptsIL-6 expressionHofbauer cellsP65 NF-κBIL-6NF-κBLeptin levelsPreeclampsia pathogenesisElevated serum interleukin-6 levelsSerum interleukin-6 levelsERK1/2 MAPKInterleukin-6 levelsPro-inflammatory phenotypeAnti-inflammatory phenotypeLeptin receptor expressionIL-6 productionPathogenesis of PEPlacental leptin productionPhosphorylation levelsERK1/2 MAPK inhibitorIL-6 regulationConcentration-dependent mannerPE patientsHuman pregnancySecond trimesterLeptin concentrations
2022
Insulin increases placental triglyceride as a potential mechanism for fetal adiposity in maternal obesity
Anam AK, Cooke KM, Dratver MB, O'Bryan JV, Perley LE, Guller SM, Hwang JJ, Taylor HS, Goedeke L, Kliman HJ, Vatner DF, Flannery CA. Insulin increases placental triglyceride as a potential mechanism for fetal adiposity in maternal obesity. Molecular Metabolism 2022, 64: 101574. PMID: 35970449, PMCID: PMC9440306, DOI: 10.1016/j.molmet.2022.101574.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisFetal adiposityFatty acid uptakeMaternal obesityObese womenNormal weightExcess adiposityVillous explantsInsulin receptorNewborns of mothersNormal-weight womenAcid uptakePlacental villous explantsTranscription factor SREBP-1Insulin-like growth factor 2Effect of insulinFatty acid oxidationPlacental triglyceridesPlacental responsesElevated triglyceridesMaternal hyperglycemiaWeight womenGrowth factor 2Diabetes riskPlacental metabolism
2021
YAP1 nuclear efflux and transcriptional reprograming follow membrane diminution upon VSV-G-induced cell fusion
Feliciano D, Ott CM, Espinosa-Medina I, Weigel AV, Benedetti L, Milano KM, Tang Z, Lee T, Kliman HJ, Guller SM, Lippincott-Schwartz J. YAP1 nuclear efflux and transcriptional reprograming follow membrane diminution upon VSV-G-induced cell fusion. Nature Communications 2021, 12: 4502. PMID: 34301937, PMCID: PMC8302681, DOI: 10.1038/s41467-021-24708-2.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAMP-Activated Protein KinasesAnimalsBiological TransportCell FusionCell LineCell Line, TumorCell MembraneCell NucleusCells, CulturedGiant CellsHEK293 CellsHumansMembrane GlycoproteinsMiceRNA-SeqSignal TransductionTranscription FactorsTranscription, GeneticViral Envelope ProteinsYAP-Signaling ProteinsConceptsCell cycle arrestCell fusionNew cellular statesPlasma membrane surface areaRNA-seq analysisCell fusion systemTranscriptional programsNutrient stressCellular statesTranscriptional changesNuclear effluxCytoplasmic glucoseExtrinsic cuesUndifferentiated cellsGlucose transporterFused cellsMechanistic insightsMembrane surface areaNew functionsEndocytosisYAP1 inhibitionEnergetic stateSyncytiaCellsVSVMaternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface
Lu-Culligan A, Chavan AR, Vijayakumar P, Irshaid L, Courchaine EM, Milano KM, Tang Z, Pope SD, Song E, Vogels CBF, Lu-Culligan WJ, Campbell KH, Casanovas-Massana A, Bermejo S, Toothaker JM, Lee HJ, Liu F, Schulz W, Fournier J, Muenker MC, Moore AJ, Team Y, Konnikova L, Neugebauer KM, Ring A, Grubaugh ND, Ko AI, Morotti R, Guller S, Kliman HJ, Iwasaki A, Farhadian SF. Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface. Med 2021, 2: 591-610.e10. PMID: 33969332, PMCID: PMC8084634, DOI: 10.1016/j.medj.2021.04.016.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionMaternal-fetal interfaceACE2 expressionNatural killerPregnant womenPlacental cellsAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSARS-CoV-2-infected womenTerm placentaSyndrome coronavirus 2 infectionCoronavirus 2 infectionPotential immune mechanismsRobust inflammatory responseRobust immune responseCoronavirus disease 2019Detectable viral RNAInterferon-related genesLower ACE2 expressionMajority of placentasPregnancy complicationsPlacental histologyHofbauer cellsEarly pregnancyImmune activation
2020
Acetaminophen Attenuates invasion and alters the expression of extracellular matrix enzymes and vascular factors in human first trimester trophoblast cells
Burman A, Garcia-Milian R, Wood M, DeWitt NA, Vasiliou V, Guller S, Abrahams VM, Whirledge S. Acetaminophen Attenuates invasion and alters the expression of extracellular matrix enzymes and vascular factors in human first trimester trophoblast cells. Placenta 2020, 104: 146-160. PMID: 33348283, DOI: 10.1016/j.placenta.2020.12.002.Peer-Reviewed Original ResearchConceptsFirst trimester trophoblast cellsHuman first trimester trophoblast cellsPrenatal acetaminophen useTrophoblast cellsAcetaminophen useTrophoblast functionsAcetaminophen exposureFetal developmentHTR-8/SVneo cellsPrenatal acetaminophen exposureAnti-inflammatory drug aspirinRecent epidemiological studiesPlacental cell typesMatrix metalloproteinases 2Expression of angiogenesisExtracellular matrix enzymesPrenatal acetaminophenCommon medicationsVascular factorsMaternal healthPlacental functionEpidemiological associationLong-term effectsCyclooxygenase-1Epidemiological studiesZika Virus-Infected Decidual Cells Elicit a Gestational Age-Dependent Innate Immune Response and Exaggerate Trophoblast Zika Permissiveness: Implication for Vertical Transmission.
Guzeloglu-Kayisli O, Guo X, Tang Z, Semerci N, Ozmen A, Larsen K, Mutluay D, Guller S, Schatz F, Kayisli UA, Lockwood CJ. Zika Virus-Infected Decidual Cells Elicit a Gestational Age-Dependent Innate Immune Response and Exaggerate Trophoblast Zika Permissiveness: Implication for Vertical Transmission. The Journal Of Immunology 2020, 205: 3083-3094. PMID: 33139490, DOI: 10.4049/jimmunol.2000713.Peer-Reviewed Original ResearchConceptsHuman decidual cellsDecidual cellsZika virusViral attachment factorsTerm decidual stromal cellsVertical transmissionDecidual cell supernatantsTerm decidual cellsInnate immune response genesInnate immune responsivenessExact pathogenic mechanismDecidual stromal cellsHuman first trimesterInnate immune responseSevere fetal defectsImmune response genesFetal sequelaeGestational ageFirst trimesterPlacental transmissionZIKV infectionCytotrophoblast culturesImmune responsivenessZika infectionLate pregnancyPeri‐implantation cytokine profile differs between singleton and twin IVF pregnancies
Simpson S, Kaislasuo J, Peng G, Aldo P, Paidas M, Guller S, Mor G, Pal L. Peri‐implantation cytokine profile differs between singleton and twin IVF pregnancies. American Journal Of Reproductive Immunology 2020, 85: e13348. PMID: 32946159, PMCID: PMC8221280, DOI: 10.1111/aji.13348.Peer-Reviewed Original ResearchConceptsMaternal serum levelsSerum levelsSingleton gestationsIL-10Twin pregnanciesC motif chemokine ligand 10General immune reactionTwin IVF pregnanciesProspective longitudinal cohortSerum cytokine concentrationsAcademic fertility centerSerial serum samplesChemokine ligand 10Implantation phaseAnti-angiogenic roleSingleton conceptionsCXCL10 levelsIVF pregnanciesIVF-ETCytokine concentrationsInterleukin-10Fertility centerSerum concentrationsTumor necrosisLongitudinal cohortNLRP3 inflammasome function and pyroptotic cell death in human placental Hofbauer cells
Abrahams VM, Tang Z, Mor G, Guller S. NLRP3 inflammasome function and pyroptotic cell death in human placental Hofbauer cells. Journal Of Reproductive Immunology 2020, 142: 103214. PMID: 33152658, PMCID: PMC7770077, DOI: 10.1016/j.jri.2020.103214.Peer-Reviewed Original ResearchConceptsHofbauer cellsCaspase-1 activationIL-1β processingIL-1βInflammasome activationFetal inflammatory response syndromeSubsequent pregnancy complicationsInflammatory response syndromeCell deathNLRP3 inflammasome activationInterleukin-1 betaIL-1β secretionInhibition of P2X7Human term placentaGasdermin D cleavageNLRP3 knockdownPlacental inflammationPyroptotic cell deathFetal inflammationHistologic chorioamnionitisPregnancy complicationsResponse syndromeNLRP3 inflammasomeProtein/gene expressionInflammatory formTrophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function
Zhang Y, Aldo P, You Y, Ding J, Kaislasuo J, Petersen JF, Lokkegaard E, Peng G, Paidas MJ, Simpson S, Pal L, Guller S, Liu H, Liao AH, Mor G. Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function. Journal Of Leukocyte Biology 2020, 108: 983-998. PMID: 32386458, PMCID: PMC8190653, DOI: 10.1002/jlb.1a0420-012rr.Peer-Reviewed Original ResearchConceptsSoluble PD-L1Macrophage polarizationTrophoblast cellsCell death ligand 1PD-L1/PDPD-1 blockageDeath ligand 1Macrophage differentiationModulates macrophage polarizationExpression/secretionDecidual macrophagesHealthy pregnancyPD-L1Pregnant womenTLR4 ligationM2 phenotypeExpression of typeFetal developmentLPS activationMacrophagesIFNPlacenta developmentLigand 1Constitutive productionGestationHuman Chorionic Gonadotropin modulates CXCL10 Expression through Histone Methylation in human decidua
Silasi M, You Y, Simpson S, Kaislasuo J, Pal L, Guller S, Peng G, Ramhorst R, Grasso E, Etemad S, Durosier S, Aldo P, Mor G. Human Chorionic Gonadotropin modulates CXCL10 Expression through Histone Methylation in human decidua. Scientific Reports 2020, 10: 5785. PMID: 32238853, PMCID: PMC7113245, DOI: 10.1038/s41598-020-62593-9.Peer-Reviewed Original ResearchConceptsHuman chorionic gonadotropinCXCL10 expressionChorionic gonadotropinPotent immune-modulatory effectsImmune system undergoesImmune modulatory effectsEndometrial stromal cellsImmune cell recruitmentMaternal-fetal interfaceImmune regulatory functionsProcess of implantationCD8 cellsCytokine profilePregnancy progressesFetal interfaceDecidual samplesImmune populationsImmune factorsHuman deciduaT cellsDecidual cellsCell recruitmentModulatory effectsEarly hormoneStromal cellsHerpesvirus-infected Hofbauer cells activate endothelial cells through an IL-1β-dependent mechanism
Hendrix P, Tang Z, Silasi M, Racicot KE, Mor G, Abrahams VM, Guller S. Herpesvirus-infected Hofbauer cells activate endothelial cells through an IL-1β-dependent mechanism. Placenta 2020, 91: 59-65. PMID: 32174308, PMCID: PMC7078070, DOI: 10.1016/j.placenta.2020.01.010.Peer-Reviewed Original ResearchConceptsHuman umbilical vein endothelial cellsHofbauer cellsIL-1βAdhesion molecule-1Placental viral infectionsIL-8Viral infectionFetal inflammationEndothelial cellsE-selectinMolecule-1IL-1 receptor antagonistVascular adhesion molecule-1Intercellular adhesion molecule-1Adverse pregnancy outcomesMHV-68 infectionIL-1β secretionICAM-1 mRNAUmbilical vein endothelial cellsUmbilical endothelial cellsPregnancy outcomesVein endothelial cellsIL-1raPlacental macrophagesHUVEC expression
2019
IL‐10 to TNFα ratios throughout early first trimester can discriminate healthy pregnancies from pregnancy losses
Kaislasuo J, Simpson S, Petersen JF, Peng G, Aldo P, Lokkegaard E, Paidas M, Pal L, Guller S, Mor G. IL‐10 to TNFα ratios throughout early first trimester can discriminate healthy pregnancies from pregnancy losses. American Journal Of Reproductive Immunology 2019, 83: e13195. PMID: 31585488, PMCID: PMC8295882, DOI: 10.1111/aji.13195.Peer-Reviewed Original ResearchConceptsWeeks of gestationIL-10Pregnancy lossHealthy pregnancyFirst trimesterTNFα ratioNormal pregnancySymptoms of miscarriageIL-10 concentrationsProspective longitudinal cohortEarly first trimesterFirst trimester lossImplantation dayIVF cohortImmunological balanceSerum levelsViable pregnancySerial bloodGestation weeksTNFα concentrationsEarly immunomodulationLongitudinal cohortEmbryo implantationPregnancySingle time pointThermal stability of cytokines: A review
Simpson S, Kaislasuo J, Guller S, Pal L. Thermal stability of cytokines: A review. Cytokine 2019, 125: 154829. PMID: 31472404, DOI: 10.1016/j.cyto.2019.154829.Peer-Reviewed Original ResearchIn Vitro Assays to Evaluate the Migration, Invasion, and Proliferation of Immortalized Human First-trimester Trophoblast Cell Lines.
Kisanga EP, Tang Z, Guller S, Whirledge S. In Vitro Assays to Evaluate the Migration, Invasion, and Proliferation of Immortalized Human First-trimester Trophoblast Cell Lines. Journal Of Visualized Experiments 2019 PMID: 30907868, DOI: 10.3791/58942.Peer-Reviewed Original ResearchConceptsCell movementCell migrationHuman first trimester trophoblast cell lineFirst trimester trophoblast cell lineIntrauterine growth restrictionCell linesTrophoblast cell linePregnancy disordersEarly pregnancyGrowth restrictionMaternal vasculatureTrophoblast migrationMigratory capacityPlacental developmentPotential mechanismsCellular changesVitro assaysInvasionTrophoblastProliferationThorough examinationMigrationAssaysIndividual factorsPregnancyDifferential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies
Lee B, Koeppel AF, Wang ET, Gonzalez TL, Sun T, Kroener L, Lin Y, Joshi NV, Ghadiali T, Turner SD, Rich SS, Farber CR, Rotter JI, Ida Chen YD, Goodarzi MO, Guller S, Harwood B, Serna TB, Williams J, Pisarska MD. Differential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies. Fertility And Sterility 2019, 111: 535-546. PMID: 30611556, PMCID: PMC7156023, DOI: 10.1016/j.fertnstert.2018.11.005.Peer-Reviewed Original ResearchConceptsFirst trimester placentaSpontaneous pregnancyIVF groupFertility treatmentMaternal medical conditionsTreatment-related factorsAcademic medical centerTranscriptomic profilesGestational age 11Fetal demographicsInfertility groupPregnancy complicationsCohort studySpontaneous conceptionMedical CenterMAIN OUTCOMEMedical conditionsPregnancyDifferent fertility treatmentsIVFLarger studyDifferential gene expressionChorionic villiGene expressionPlacenta
2018
Excess glucose induce trophoblast inflammation and limit cell migration through HMGB1 activation of Toll‐Like receptor 4
Heim KR, Mulla MJ, Potter JA, Han CS, Guller S, Abrahams VM. Excess glucose induce trophoblast inflammation and limit cell migration through HMGB1 activation of Toll‐Like receptor 4. American Journal Of Reproductive Immunology 2018, 80: e13044. PMID: 30175447, DOI: 10.1111/aji.13044.Peer-Reviewed Original ResearchConceptsToll-like receptor 4High mobility group box 1Damage-associated molecular patternsHMGB1 activationIL-1βIL-8Trophoblast responsesReceptor 4Human first trimester trophoblast cell lineFirst trimester trophoblast cell lineInflammatory IL-8Risk of preeclampsiaGroup box 1Uric acidIL-1β responseExcess glucoseTrophoblast cell lineCell migrationTrophoblast inflammationPregnancy outcomesTLR4 antagonistLPS-RSIL-6SFlt-1HMGB1 inhibitorGlucocorticoid signaling regulates cell invasion and migration in the human first‐trimester trophoblast cell line Sw.71
Kisanga EP, Tang Z, Guller S, Whirledge S. Glucocorticoid signaling regulates cell invasion and migration in the human first‐trimester trophoblast cell line Sw.71. American Journal Of Reproductive Immunology 2018, 80: e12974. PMID: 29774963, DOI: 10.1111/aji.12974.Peer-Reviewed Original ResearchConceptsGene expression profilesSERPINE1 promoterPolymerase IITranscriptional regulationGlucocorticoid receptorCell movementTranscriptional profilesGlucocorticoid treatmentExpression profilesMicroarray analysisStress responseCell invasionPrimary mediatorPathogenesis of preeclampsiaCell proliferationEffects of glucocorticoidsExtravillous trophoblast functionsGlucocorticoid signalingSynthetic glucocorticoid dexamethasoneGenesTrophoblast functionsAdrenal axisInvasionTrophoblast tissueGlucocorticoid dexamethasoneIn memoriam: Mortimer Levitz) Levitz – Mortimer, PhD. (May 11, 1921 to February 7, 2018)
Guller S. In memoriam: Mortimer Levitz) Levitz – Mortimer, PhD. (May 11, 1921 to February 7, 2018). Steroids 2018, 148: 125-126. PMID: 29750995, DOI: 10.1016/j.steroids.2018.05.004.Peer-Reviewed Original Research
2017
Low molecular weight heparin and aspirin exacerbate human endometrial endothelial cell responses to antiphospholipid antibodies
Quao ZC, Tong M, Bryce E, Guller S, Chamley LW, Abrahams VM. Low molecular weight heparin and aspirin exacerbate human endometrial endothelial cell responses to antiphospholipid antibodies. American Journal Of Reproductive Immunology 2017, 79 PMID: 29135051, PMCID: PMC5728699, DOI: 10.1111/aji.12785.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, AntiphospholipidAntiphospholipid SyndromeAspirinBeta 2-Glycoprotein ICells, CulturedChemokinesDisease ProgressionDrug Therapy, CombinationEndometriumEndothelial CellsFemaleHeparin, Low-Molecular-WeightHumansMembrane ProteinsNeovascularization, PhysiologicPregnancyPregnancy ComplicationsTrophoblastsVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-1ConceptsLow molecular weight heparinHuman endometrial endothelial cellsMolecular weight heparinUterine endotheliumAntiphospholipid antibodiesWeight heparinInfluence of LMWHLow dose low molecular weight heparinAnti-angiogenic sFlt-1Chemokine MCP-1Endometrial endothelial cellsEffects of aPLSFlt-1 releaseAngiogenic factor secretionObstetric APSPregnancy complicationsControl IgGChemokine profilesEndothelium dysfunctionChemokine secretionPro-angiogenic VEGFCombination therapySFlt-1Impaired placentationMCP-1Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation.
Cross SN, Potter JA, Aldo P, Kwon JY, Pitruzzello M, Tong M, Guller S, Rothlin CV, Mor G, Abrahams VM. Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation. The Journal Of Immunology 2017, 199: 2885-2895. PMID: 28916522, PMCID: PMC5659726, DOI: 10.4049/jimmunol.1700870.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsC-Mer Tyrosine KinaseCells, CulturedChorioamnionitisExtraembryonic MembranesFemaleGammaherpesvirinaeHerpesviridae InfectionsHerpesvirus 2, HumanHumansImmunizationInflammasomesIntercellular Signaling Peptides and ProteinsInterleukin-1betaLipopolysaccharidesMiceMice, Inbred C57BLMice, KnockoutPregnancyPremature BirthProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesConceptsFetal membranesViral infectionImmune responseTAM receptorsSubsequent preterm birthAdverse pregnancy outcomesIL-1β productionIL-1β responseHerpes viral infectionsInnate immune responseVivo mouse modelHuman fetal membranesAggravated inflammationIL-1β processingPregnancy outcomesPreterm birthAssociated complicationsPremature rupturePregnant womenLocal infectionInflammasome activationMerTK inhibitionMouse modelBacterial LPSLigand expression