2024
Mechano-inhibition of endocytosis sensitizes cancer cells to Fas-induced Apoptosis
Kural M, Djakbarova U, Cakir B, Tanaka Y, Chan E, Arteaga Muniz V, Madraki Y, Qian H, Park J, Sewanan L, Park I, Niklason L, Kural C. Mechano-inhibition of endocytosis sensitizes cancer cells to Fas-induced Apoptosis. Cell Death & Disease 2024, 15: 440. PMID: 38909035, PMCID: PMC11193792, DOI: 10.1038/s41419-024-06822-3.Peer-Reviewed Original ResearchConceptsFas-induced apoptosisCell surface Fas expressionDeath receptor FasInhibition of endocytosisSurface Fas expressionPlasma membrane tensionCancer cell apoptosisEndocytosis dynamicsApoptotic signalingReceptor FasGlioblastoma cell growthFas expressionPlasma membraneCell growthEndocytosisXenograft mouse modelSoluble FasLCell apoptosisFasApoptosisRho-kinase inhibitorCancer cellsMembrane tensionNonmalignant cellsInduce tumor regression
2023
Scalable production of tissue-like vascularized liver organoids from human PSCs
Harrison S, Siller R, Tanaka Y, Chollet M, de la Morena-Barrio M, Xiang Y, Patterson B, Andersen E, Bravo-Pérez C, Kempf H, Åsrud K, Lunov O, Dejneka A, Mowinckel M, Stavik B, Sandset P, Melum E, Baumgarten S, Bonanini F, Kurek D, Mathapati S, Almaas R, Sharma K, Wilson S, Skottvoll F, Boger I, Bogen I, Nyman T, Wu J, Bezrouk A, Cizkova D, Corral J, Mokry J, Zweigerdt R, Park I, Sullivan G. Scalable production of tissue-like vascularized liver organoids from human PSCs. Experimental & Molecular Medicine 2023, 55: 2005-2024. PMID: 37653039, PMCID: PMC10545717, DOI: 10.1038/s12276-023-01074-1.Peer-Reviewed Original ResearchConceptsExtracellular matrixSingle-cell RNA sequencingBasic developmental biologyEmbryonic liver developmentPost-translational modificationsLiver-like functionsCostly growth factorsOrganoid modelsKey liver functionsCellular diversityCellular repertoireDevelopmental biologyCellular complexityN-glycosylationRNA sequencingDe novo vascularizationNumber of tissuesProtein productionSerum protein productionLiver developmentHuman PSCsDrug toxicity assessmentOrganoidsSmall moleculesGrowth factor
2022
Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
Zhang H, Li B, Huang Q, López-Giráldez F, Tanaka Y, Lin Q, Mehta S, Wang G, Graham M, Liu X, Park I, Eichmann A, Min W, Zhou J. Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas. Nature Communications 2022, 13: 7637. PMID: 36496409, PMCID: PMC9741628, DOI: 10.1038/s41467-022-35262-w.Peer-Reviewed Original ResearchConceptsMitochondrial dysfunctionThioredoxin 2Single-cell RNA-seq analysisRNA-seq analysisMutant miceNuclear genesMitochondrial proteinsMitochondrial localizationHuman retinal diseasesTranscriptional factorsGene expressionMutant retinasMitochondrial activityExtracellular matrixNovel mechanismVascular maturationArteriovenous malformationsGenetic deficiencyVessel growthSmad2Mouse retinaVascular malformationsMechanistic studiesBasement membraneRetinal vascular malformationsHuman Down syndrome microglia are up for a synaptic feast
Kiral FR, Park IH. Human Down syndrome microglia are up for a synaptic feast. Cell Stem Cell 2022, 29: 1007-1008. PMID: 35803219, DOI: 10.1016/j.stem.2022.06.008.Peer-Reviewed Original ResearchLive isolation of naïve ESCs via distinct glucose metabolism and stored glycogen
Kim KT, Oh JY, Park S, Kim SM, Benjamin P, Park IH, Chun KH, Chang YT, Cha HJ. Live isolation of naïve ESCs via distinct glucose metabolism and stored glycogen. Metabolic Engineering 2022, 72: 97-106. PMID: 35283260, DOI: 10.1016/j.ymben.2022.03.003.Peer-Reviewed Original ResearchExpression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids
Cakir B, Tanaka Y, Kiral FR, Xiang Y, Dagliyan O, Wang J, Lee M, Greaney AM, Yang WS, duBoulay C, Kural MH, Patterson B, Zhong M, Kim J, Bai Y, Min W, Niklason LE, Patra P, Park IH. Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids. Nature Communications 2022, 13: 430. PMID: 35058453, PMCID: PMC8776770, DOI: 10.1038/s41467-022-28043-y.Peer-Reviewed Original ResearchConceptsHuman embryonic stem cellsHuman cortical organoidsTranscription factor PUSingle-cell RNA sequencingMicroglia-like cellsSingle-cell transcriptomicsEmbryonic stem cellsDisease stage IIIRole of microgliaAD-associated genesExpression of genesCortical organoidsNeurodegenerative disordersRNA sequencingMolecular damageIntact complementStem cellsDysfunction of microgliaFunctional microgliaReduced expressionGenesCell clustersExpressionChemokine systemHuman microglia
2021
Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts
Cho J, Kim S, Lee H, Rah W, Cho HC, Kim NK, Bae S, Shin DH, Lee MG, Park IH, Tanaka Y, Shin E, Yi H, Han JW, Hwang PTJ, Jun HW, Park HJ, Cho K, Lee SW, Jung JK, Levit RD, Sussman MA, Harvey RP, Yoon YS. Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts. Nature Biomedical Engineering 2021, 5: 880-896. PMID: 34426676, PMCID: PMC8809198, DOI: 10.1038/s41551-021-00783-0.Peer-Reviewed Original ResearchConceptsDirect reprogrammingMouse tail-tip fibroblastsBone morphogenetic protein 4Smooth muscle cellsTail-tip fibroblastsMuscle cellsSomatic cellsEndothelial cellsReprogrammingCell typesTissue-like structuresMouse fibroblastsProtein 4Gap junctionsCardiovascular tissuesVessel formationDisease modellingDrug discoveryImmature characteristicsFibroblastsCellsMouse heartsCardiomyocytesTissueHost cardiomyocytesVulnerability of cholecystokinin-expressing GABAergic interneurons in the unilateral intrahippocampal kainate mouse model of temporal lobe epilepsy
Kang YJ, Clement EM, Park IH, Greenfield LJ, Smith BN, Lee SH. Vulnerability of cholecystokinin-expressing GABAergic interneurons in the unilateral intrahippocampal kainate mouse model of temporal lobe epilepsy. Experimental Neurology 2021, 342: 113724. PMID: 33915166, PMCID: PMC8192495, DOI: 10.1016/j.expneurol.2021.113724.Peer-Reviewed Original ResearchConceptsTemporal lobe epilepsyIntrahippocampal kainate mouse modelVentral CA1 regionEpileptic miceCA1 pyramidal cellsSclerotic hippocampusPyramidal cellsSham controlsSpontaneous seizuresLobe epilepsyCA1 regionMouse modelFrequency of IPSCsNetwork oscillationsRecurrent spontaneous seizuresNumber of boutonsHippocampal theta oscillationsIpsilateral hippocampusElectrical recordingsVentral hippocampusCA1 layerGABAergic interneuronsStratum pyramidaleDorsal hippocampusBehavioral comorbiditiesRegional specification and complementation with non-neuroectodermal cells in human brain organoids
Tanaka Y, Park IH. Regional specification and complementation with non-neuroectodermal cells in human brain organoids. Journal Of Molecular Medicine 2021, 99: 489-500. PMID: 33651139, PMCID: PMC8026433, DOI: 10.1007/s00109-021-02051-9.Peer-Reviewed Original ResearchAnimalsBrainCellular Reprogramming TechniquesEmbryoid BodiesEndothelial CellsFetusFibroblast Growth Factor 2Hedgehog ProteinsHuman Umbilical Vein Endothelial CellsHumansInduced Pluripotent Stem CellsIntercellular Signaling Peptides and ProteinsMicrogliaNeuronsOrgan SpecificityOrganogenesisOrganoidsRetinaSpinal CordWnt Signaling Pathway
2020
Reprogramming progressive cells display low CAG promoter activity
Hu X, Wu Q, Zhang J, Kim J, Chen X, Hartman AA, Eastman AE, Park I, Guo S. Reprogramming progressive cells display low CAG promoter activity. Stem Cells 2020, 39: 43-54. PMID: 33075202, PMCID: PMC7821215, DOI: 10.1002/stem.3295.Peer-Reviewed Original ResearchGenes causing congenital hydrocephalus: Their chromosomal characteristics of telomere proximity and DNA compositions
McKnight I, Hart C, Park IH, Shim JW. Genes causing congenital hydrocephalus: Their chromosomal characteristics of telomere proximity and DNA compositions. Experimental Neurology 2020, 335: 113523. PMID: 33157092, PMCID: PMC7750280, DOI: 10.1016/j.expneurol.2020.113523.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCentral nervous systemFamilial Parkinson's diseaseAlzheimer's diseaseCausative genesGenome Data ViewerHuman genetic mutationsDisease-susceptible genesHigh mutation rateGenetic mutationsHuman congenital hydrocephalusHuman clinical studiesPutative genesHuman genesGenomic informationT contentChromosomal characteristicsDNA compositionGenetic basisHigh adenineMutation rateClinical studiesGenesPreclinical modelsThymine contentMural Cell-Specific Deletion of Cerebral Cavernous Malformation 3 in the Brain Induces Cerebral Cavernous Malformations
Wang K, Zhang H, He Y, Jiang Q, Tanaka Y, Park IH, Pober JS, Min W, Zhou HJ. Mural Cell-Specific Deletion of Cerebral Cavernous Malformation 3 in the Brain Induces Cerebral Cavernous Malformations. Arteriosclerosis Thrombosis And Vascular Biology 2020, 40: 2171-2186. PMID: 32640906, DOI: 10.1161/atvbaha.120.314586.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosis Regulatory ProteinsBrainCell CommunicationCell MovementCells, CulturedCoculture TechniquesEndothelial CellsFemaleFocal AdhesionsGene DeletionGenetic Predisposition to DiseaseHemangioma, Cavernous, Central Nervous SystemHumansMaleMembrane ProteinsMice, KnockoutMicrovesselsMyocytes, Smooth MusclePaxillinPericytesPhenotypeProtein StabilityProto-Oncogene ProteinsSignal TransductionConceptsCerebral cavernous malformationsBrain mural cellsCCM lesionsMural cellsCavernous malformationsSevere brain hemorrhageCCM pathogenesisSmooth muscle cellsWeeks of ageCell-specific deletionMural cell coverageBrain pericytesBrain hemorrhageNeonatal stageBrain vasculatureLesionsEntire brainMuscle cellsCerebral cavernous malformation 3Endothelial cellsMicePericytesSpecific deletionAdhesion formationPathogenesisDysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons
Xiang Y, Tanaka Y, Patterson B, Hwang SM, Hysolli E, Cakir B, Kim KY, Wang W, Kang YJ, Clement EM, Zhong M, Lee SH, Cho YS, Patra P, Sullivan GJ, Weissman SM, Park IH. Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons. Molecular Cell 2020, 79: 84-98.e9. PMID: 32526163, PMCID: PMC7375197, DOI: 10.1016/j.molcel.2020.05.016.Peer-Reviewed Original ResearchConceptsMECP2 mutant neuronsEnhancer-promoter interactionsRett syndromeRTT-like phenotypesChromatin bindingMeCP2 functionMethyl-CpGAbnormal transcriptionRTT etiologyMutant neuronsBET inhibitorsPotential therapeutic opportunitiesMECP2 mutationsProtein 2Human brain organoidsFunctional phenotypeJQ1BRD4Therapeutic opportunitiesBrain organoidsFunction underliesMutationsPhenotypeHuman brain culturesCritical driverImplantation of the clinical‐grade human neural stem cell line, CTX0E03, rescues the behavioral and pathological deficits in the quinolinic acid‐lesioned rodent model of Huntington's disease
Yoon Y, Kim HS, Jeon I, Noh J, Park HJ, Lee S, Park I, Stevanato L, Hicks C, Corteling R, Barker RA, Sinden JD, Song J. Implantation of the clinical‐grade human neural stem cell line, CTX0E03, rescues the behavioral and pathological deficits in the quinolinic acid‐lesioned rodent model of Huntington's disease. Stem Cells 2020, 38: 936-947. PMID: 32374064, PMCID: PMC7496241, DOI: 10.1002/stem.3191.Peer-Reviewed Original ResearchConceptsMedium spiny neuronsNeural stem cell lineHuntington's diseaseQuinolinic acid (QA) lesion rat modelChronic ischemic stroke patientsStriatal medium spiny neuronsCell linesImmortalized neural stem cell linesIschemic stroke patientsDisease-modifying therapiesSignals of efficacyGlial scar formationHost brain tissueHuman neural stem cell lineSignificant behavioral improvementAutosomal dominant neurodegenerative diseaseCTX0E03 cellsEndogenous neurogenesisBDNF expressionGABAergic neuronsHD patientsStroke patientsFluoro-GoldRetrograde labelSpiny neurons
2019
Engineering of human brain organoids with a functional vascular-like system
Cakir B, Xiang Y, Tanaka Y, Kural MH, Parent M, Kang YJ, Chapeton K, Patterson B, Yuan Y, He CS, Raredon MSB, Dengelegi J, Kim KY, Sun P, Zhong M, Lee S, Patra P, Hyder F, Niklason LE, Lee SH, Yoon YS, Park IH. Engineering of human brain organoids with a functional vascular-like system. Nature Methods 2019, 16: 1169-1175. PMID: 31591580, PMCID: PMC6918722, DOI: 10.1038/s41592-019-0586-5.Peer-Reviewed Original ResearchConceptsHuman cortical organoidsBlood-brain barrier characteristicsTrans-endothelial electrical resistanceVasculature-like structuresHuman brain organoidsHuman brain developmentCortical organoidsFunctional maturationPrenatal brainBrain diseasesBrain developmentHuman embryonic stem cellsBlood vesselsBrain organoidsTight junctionsDiseaseStem cellsOrganoidsVariant 2Nutrient transportersNutrient deliveryCellsEndotheliumMicrovasculatureThe critical role of persistent sodium current in hippocampal gamma oscillations
Kang YJ, Clement EM, Sumsky SL, Xiang Y, Park IH, Santaniello S, Greenfield LJ, Garcia-Rill E, Smith BN, Lee SH. The critical role of persistent sodium current in hippocampal gamma oscillations. Neuropharmacology 2019, 162: 107787. PMID: 31550457, PMCID: PMC6952064, DOI: 10.1016/j.neuropharm.2019.107787.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCA1 Region, HippocampalCalcium-Calmodulin-Dependent Protein Kinase Type 2Excitatory Amino Acid AntagonistsExcitatory Postsynaptic PotentialsGABAergic NeuronsGamma RhythmHippocampusInhibitory Postsynaptic PotentialsInterneuronsMiceOptogeneticsParvalbuminsPatch-Clamp TechniquesPhenytoinPyramidal CellsRiluzoleSodiumVoltage-Gated Sodium Channel BlockersConceptsParvalbumin-expressing basket cellsHippocampal gamma oscillationsCortical gamma oscillationsGABAergic interneuronsGamma oscillationsPyramidal cellsNon-inactivating sodium currentExcitatory cellsSodium currentWhole-cell patch-clamp recordingsNetwork oscillationsPatch-clamp recordingsPersistent sodium currentGamma network oscillationsAnticonvulsant efficacyGamma frequency rangeEpilepsy patientsBasket cellsCognitive impairmentAction potentialsSynaptic propertiesSynaptic interactionsOptogenetic stimulationElectrophysiological approachesCA1 network
2018
Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a
Kim KY, Tanaka Y, Su J, Cakir B, Xiang Y, Patterson B, Ding J, Jung YW, Kim JH, Hysolli E, Lee H, Dajani R, Kim J, Zhong M, Lee JH, Skalnik D, Lim JM, Sullivan GJ, Wang J, Park IH. Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a. Nature Communications 2018, 9: 2583. PMID: 29968706, PMCID: PMC6030064, DOI: 10.1038/s41467-018-04818-0.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCCAAT-Enhancer-Binding ProteinsCellular ReprogrammingCellular Reprogramming TechniquesChimeraDNA MethylationEpigenesis, GeneticFemaleFibroblastsGene Knockout TechniquesHEK293 CellsHistone CodeHistone-Lysine N-MethyltransferaseHistonesHumansMaleMesodermMiceMouse Embryonic Stem CellsNeural PlateNuclear ProteinsPrimary Cell CultureRecombinant ProteinsUbiquitin-Protein LigasesConceptsEmbryonic stem cellsUnique epigenetic statesBivalent histone modificationsRecruitment of DNMT1Bivalent histone marksCell typesDNA-binding proteinsSpecialized cell typesStem cellsPluripotent stem cellsTrithorax groupBivalent domainsMesoderm specificationCOMPASS complexHeterochromatin formationEpigenetic stateCell specificationHistone marksLineage specificationHistone modificationsEpigenetic regulationSpecific lineagesDNA methylationTranscriptional marksEpigenetic changes
2017
Enhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell–Derived Endothelial Cells Encapsulated in a Nanomatrix Gel
Lee SJ, Sohn YD, Andukuri A, Kim S, Byun J, Han JW, Park IH, Jun HW, Yoon YS. Enhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell–Derived Endothelial Cells Encapsulated in a Nanomatrix Gel. Circulation 2017, 136: 1939-1954. PMID: 28972000, PMCID: PMC5685906, DOI: 10.1161/circulationaha.116.026329.Peer-Reviewed Original ResearchConceptsCell survivalHPSC-ECsHuman pluripotent stem cell-derived endothelial cellsEndothelial lineage differentiationGlycogen synthase kinase-3β inhibitorHuman pluripotent stem cellsStem cell-derived endothelial cellsGrowth factorDifferentiation of hPSCsLonger cell survivalEndothelial cellsCell-derived endothelial cellsVessel formationPluripotent stem cell-derived endothelial cellsBetter perfusion recoveryPluripotent stem cellsNanomatrix gelLong-term cell survivalMesodermal lineagesLineage differentiationHuman umbilical vein endothelial cellsUmbilical vein endothelial cellsDifferentiation systemFibroblast growth factorBasic fibroblast growth factor
2016
Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2
Lee S, Park C, Han JW, Kim JY, Cho K, Kim EJ, Kim S, Lee SJ, Oh SY, Tanaka Y, Park IH, An HJ, Shin CM, Sharma S, Yoon YS. Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2. Circulation Research 2016, 120: 848-861. PMID: 28003219, PMCID: PMC5336520, DOI: 10.1161/circresaha.116.309833.Peer-Reviewed Original ResearchConceptsEndothelial cellsPostnatal cellsCell therapyDermal fibroblastsMature endothelial cellsNew vessel formationEndothelial featuresHuman endothelial cellsHindlimb ischemiaIschemic hindlimbPathophysiological investigationsEndothelial transcription factorImmature phenotypeDay 7Therapeutic potentialVascular incorporationProangiogenic effectsMature phenotypeEndothelial characteristicsIschemiaVessel formationHuman dermal fibroblastsTranscription factorsTherapyDisease investigationSingle cell transcriptomics reveals unanticipated features of early hematopoietic precursors
Yang J, Tanaka Y, Seay M, Li Z, Jin J, Garmire LX, Zhu X, Taylor A, Li W, Euskirchen G, Halene S, Kluger Y, Snyder MP, Park IH, Pan X, Weissman SM. Single cell transcriptomics reveals unanticipated features of early hematopoietic precursors. Nucleic Acids Research 2016, 45: 1281-1296. PMID: 28003475, PMCID: PMC5388401, DOI: 10.1093/nar/gkw1214.Peer-Reviewed Original ResearchConceptsHematopoietic stem cellsPrecursor cellsInduction of anemiaInterferon response genesG2/M phaseEarly precursor cellsHomeostatic cellsStages of differentiationTranscription factorsSurface markersCell cycle progressionLong-term hematopoietic stem cellsSpecific augmentationAnemic miceMarked increaseEarly hematopoietic precursorsHematopoietic precursorsStem cellsCycle progressionM phaseSingle-cell transcriptomicsCellsCell differentiationHematopoietic stressLineage-specific transcription factors