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
Expression 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
2020
Mural 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 formationPathogenesisGeneration of Regionally Specified Human Brain Organoids Resembling Thalamus Development
Xiang Y, Cakir B, Park IH. Generation of Regionally Specified Human Brain Organoids Resembling Thalamus Development. STAR Protocols 2020, 1: 100001. PMID: 33103124, PMCID: PMC7580078, DOI: 10.1016/j.xpro.2019.100001.Peer-Reviewed Original ResearchMeSH KeywordsBody PatterningCells, CulturedHumansModels, BiologicalOrganoidsPluripotent Stem CellsThalamus
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 deliveryCellsEndotheliumMicrovasculature
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 investigationNeural Stem Cells Restore Hair Growth through Activation of the Hair Follicle Niche
Hwang I, Choi KA, Park HS, Jeong H, Kim JO, Seol KC, Kwon HJ, Park IH, Hong S. Neural Stem Cells Restore Hair Growth through Activation of the Hair Follicle Niche. Cell Transplantation 2016, 25: 1439-1451. PMID: 27110030, DOI: 10.3727/096368916x691466.Peer-Reviewed Original ResearchConceptsInsulin-like growth factor-1Shaven dorsal skinNeural stem cellsVascular endothelial growth factorDermal papilla cellsHepatocyte growth factorKeratinocyte growth factorGrowth factorHair follicle nicheHair growthDorsal skinStem cellsAnagen phaseGrowth factor-1Endothelial growth factorGrowth factor pathwaysCombined growth factorsMolecular signaling pathwaysPharmacological therapyHair regrowthHair shaft lengthBone morphogenetic protein family membersNSC treatmentProtein family membersHair follicle stem cells
2014
X Chromosome of Female Cells Shows Dynamic Changes in Status during Human Somatic Cell Reprogramming
Kim KY, Hysolli E, Tanaka Y, Wang B, Jung YW, Pan X, Weissman SM, Park IH. X Chromosome of Female Cells Shows Dynamic Changes in Status during Human Somatic Cell Reprogramming. Stem Cell Reports 2014, 2: 896-909. PMID: 24936474, PMCID: PMC4050354, DOI: 10.1016/j.stemcr.2014.04.003.Peer-Reviewed Original ResearchConceptsX chromosome stateInactive X chromosomeActive X chromosomeX chromosomeChromosome stateHuman somatic cell reprogrammingIPSC clonesSomatic cell reprogrammingX chromosome reactivationStem cellsEmbryonic stem cellsPluripotent stem cellsHuman iPSC clonesEpigenetic stateCell reprogrammingFemale iPSCsFemale cellsChromosomesHuman iPSCsParental cellsDisease modelingDynamic changesRobust reactivationIPSCsClones
2013
Transcriptional regulation in pluripotent stem cells by methyl CpG-binding protein 2 (MeCP2)
Tanaka Y, Kim KY, Zhong M, Pan X, Weissman SM, Park IH. Transcriptional regulation in pluripotent stem cells by methyl CpG-binding protein 2 (MeCP2). Human Molecular Genetics 2013, 23: 1045-1055. PMID: 24129406, PMCID: PMC3900111, DOI: 10.1093/hmg/ddt500.Peer-Reviewed Original ResearchConceptsPluripotent stem cellsMutant MECP2X chromosomeMethyl-CpGStem cellsGene expressionLong-range chromatin interactionsFundamental cellular physiologyRett syndromeMitochondrial membrane proteinInactive X chromosomeProtein 2Chromatin interactionsTranscriptional regulationTranscription regulatorsCellular physiologyTranscriptome analysisLoss of functionMembrane proteinsMeCP2 resultsDe novo mutationsRegulatory mechanismsMeCP2ChromosomesRTT patientsNotch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells
Lee JB, Werbowetski-Ogilvie TE, Lee JH, McIntyre BA, Schnerch A, Hong SH, Park IH, Daley GQ, Bernstein ID, Bhatia M. Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells. Blood 2013, 122: 1162-1173. PMID: 23733337, DOI: 10.1182/blood-2012-12-471649.Peer-Reviewed Original ResearchMeSH KeywordsApoptosisBasic Helix-Loop-Helix Transcription FactorsBiomarkersBlotting, WesternCell DifferentiationCell MovementCell ProliferationCells, CulturedDermisEmbryonic Stem CellsEndothelium, VascularFibroblastsFlow CytometryGene Expression ProfilingGene Expression RegulationHematopoiesisHematopoietic Stem CellsHomeodomain ProteinsHumansImmunoenzyme TechniquesInduced Pluripotent Stem CellsOligonucleotide Array Sequence AnalysisReceptor, Notch1Receptors, NotchRNA, Small InterferingSignal TransductionTranscription Factor HES-1ConceptsCell fate decisionsFate decisionsPluripotent stem cellsHematopoietic lineage specificationEarly human hematopoiesisFunction of NotchStem cellsHuman pluripotent stem cellsInduced pluripotent stem cellsRole of NotchEarly human developmentCommitted hematopoietic progenitorsFate specificationLineage specificationCellular processesNotch receptorsNotch signalingHematopoietic lineagesNotch pathwayBipotent precursorsNotch ligandsHuman hematopoiesisHuman embryonicUnappreciated roleToggle switchPluripotent Stem Cell Models of Shwachman-Diamond Syndrome Reveal a Common Mechanism for Pancreatic and Hematopoietic Dysfunction
Tulpule A, Kelley JM, Lensch MW, McPherson J, Park IH, Hartung O, Nakamura T, Schlaeger TM, Shimamura A, Daley GQ. Pluripotent Stem Cell Models of Shwachman-Diamond Syndrome Reveal a Common Mechanism for Pancreatic and Hematopoietic Dysfunction. Cell Stem Cell 2013, 12: 727-736. PMID: 23602541, PMCID: PMC3755012, DOI: 10.1016/j.stem.2013.04.002.Peer-Reviewed Original ResearchConceptsHuman embryonic stem cellsPluripotent stem cell modelsStem cell modelShwachman-Diamond syndromeHuman pluripotent stem cell modelSBDS protein expressionEmbryonic stem cellsDiamond syndrome (SBDS) geneStem cell linesHematopoietic dysfunctionPluripotent stem cell lineHematopoietic phenotypeInduced pluripotent stem cell lineHematopoietic differentiationCell modelTransgene rescueShwachman-BodianSyndrome geneHuman diseasesElevated protease levelsNovel insightsMechanistic linkStem cellsEnhanced apoptosisProtein expressionTransformation of somatic cells into stem cell‐like cells under a stromal niche
Lee ST, Gong SP, Yum KE, Lee EJ, Lee CH, Choi JH, Kim DY, Han H, Kim K, Hysolli E, Ahn JY, Park I, Han JY, Jeong J, Lim JM. Transformation of somatic cells into stem cell‐like cells under a stromal niche. The FASEB Journal 2013, 27: 2644-2656. PMID: 23580613, PMCID: PMC4050423, DOI: 10.1096/fj.12-223065.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell AggregationCell DedifferentiationCell FusionCells, CulturedChromosome AberrationsCoculture TechniquesEmbryo, MammalianEmbryonic Stem CellsFemaleFibroblastsGene Expression ProfilingInduced Pluripotent Stem CellsKaryotypingMiceMice, Inbred C57BLMice, Inbred CBAMice, Inbred DBAMice, Inbred ICRMicroscopy, Electron, TransmissionOligonucleotide Array Sequence AnalysisOvarySpecies SpecificityStem Cell NicheStem CellsConceptsEmbryonic stem cellsColony-forming fibroblastsParthenogenetic embryonic stem cellsSomatic cellsGenomic single nucleotide polymorphismsAcquisition of pluripotencySomatic cell plasticityPluripotency gene expressionStem cellsInner cell massStem cell-like cellsCell cycle-related proteinsPluripotent stem cellsSomatic genomeCycle-related proteinsGenomic plasticityCell-like cellsSingle nucleotide polymorphismsCell plasticityESC coloniesGenetic manipulationHeterologous recombinationEmbryonic fibroblastsImprinting patternGene expression
2012
Modeling Supravalvular Aortic Stenosis Syndrome With Human Induced Pluripotent Stem Cells
Ge X, Ren Y, Bartulos O, Lee MY, Yue Z, Kim KY, Li W, Amos PJ, Bozkulak EC, Iyer A, Zheng W, Zhao H, Martin KA, Kotton DN, Tellides G, Park IH, Yue L, Qyang Y. Modeling Supravalvular Aortic Stenosis Syndrome With Human Induced Pluripotent Stem Cells. Circulation 2012, 126: 1695-1704. PMID: 22914687, PMCID: PMC3586776, DOI: 10.1161/circulationaha.112.116996.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAortic Stenosis, SupravalvularCells, CulturedChildHumansInduced Pluripotent Stem CellsMaleMiceWilliams SyndromeConceptsActin filament bundlesSmooth muscle αSmooth muscle cellsExtracellular signal-regulated kinase 1/2Muscle αFilament bundlesSignal-regulated kinase 1/2Four-nucleotide insertionDisease mechanismsContractile smooth muscle cellsStem cell linesPluripotent stem cellsPluripotent stem cell linePlatelet-derived growth factorRhoA signalingVascular smooth muscle cellsRecombinant proteinsKinase 1/2Elastin geneELN geneWilliams-Beuren syndromeBrdU analysisSupravalvular aortic stenosisStem cellsHigh proliferation rateOvercoming reprogramming resistance of Fanconi anemia cells
Müller LU, Milsom MD, Harris CE, Vyas R, Brumme KM, Parmar K, Moreau LA, Schambach A, Park IH, London WB, Strait K, Schlaeger T, DeVine AL, Grassman E, D'Andrea A, Daley GQ, Williams DA. Overcoming reprogramming resistance of Fanconi anemia cells. Blood 2012, 119: 5449-5457. PMID: 22371882, PMCID: PMC3369681, DOI: 10.1182/blood-2012-02-408674.Peer-Reviewed Original ResearchConceptsFA cellsFA pathwayFA DNA repair pathwayFanconi anemiaDNA double-strand breaksFanconi anemia cellsStem cellsDNA repair pathwaysDouble-strand breaksDisease-specific iPSCsPluripotent stem cellsFuture translational applicationsGenomic integrityHuman primary cellsHematopoietic stem cellsHematopoietic differentiationChromosomal instabilityMolecular characterizationGene correctionTransgenic expressionDNA damageGenetic correctionHematopoietic cellsPrimary cellsPathway
2010
Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome)
Tolar J, Park IH, Xia L, Lees CJ, Peacock B, Webber B, McElmurry RT, Eide CR, Orchard PJ, Kyba M, Osborn MJ, Lund TC, Wagner JE, Daley GQ, Blazar BR. Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome). Blood 2010, 117: 839-847. PMID: 21037085, PMCID: PMC3035077, DOI: 10.1182/blood-2010-05-287607.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBone Marrow CellsCell DifferentiationCells, CulturedChild, PreschoolDNA MethylationHEK293 CellsHematopoietic SystemHomeodomain ProteinsHumansIduronidaseInduced Pluripotent Stem CellsInfantKeratinocytesKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMesodermMiceMucopolysaccharidosis INanog Homeobox ProteinOctamer Transcription Factor-3Promoter Regions, GeneticProto-Oncogene Proteins c-mycSOXB1 Transcription FactorsStromal CellsTransfectionConceptsHematopoietic cell transplantationMPS IHMucopolysaccharidosis type IL-iduronidaseNonhematopoietic cellsStem cellsLife-saving measureInduced pluripotent stem cellsAutologous stem cellsAutologous hematopoietic graftsType IPluripotent stem cellsAllogeneic transplantationSignificant morbidityImmunologic complicationsInsidious onsetCell transplantationHematopoietic graftsImmune reactionsAnatomical sitesCongenital deficiencyIdeal graftDonor cellsLysosomal storageKnown benefitsHuman Pluripotent Stem Cells Produce Natural Killer Cells That Mediate Anti-HIV-1 Activity by Utilizing Diverse Cellular Mechanisms
Ni Z, Knorr DA, Clouser CL, Hexum MK, Southern P, Mansky LM, Park IH, Kaufman DS. Human Pluripotent Stem Cells Produce Natural Killer Cells That Mediate Anti-HIV-1 Activity by Utilizing Diverse Cellular Mechanisms. Journal Of Virology 2010, 85: 43-50. PMID: 20962093, PMCID: PMC3014194, DOI: 10.1128/jvi.01774-10.Peer-Reviewed Original ResearchConceptsNK cellsHIV/AIDSAnti-HIV-1 immunityHIV-1-infected individualsAntibody-dependent cellular cytotoxicityTumor cellsCEM-GFP cellsFunctional NK cellsAnti-HIV-1 activityNatural killer cellsHIV-1 infectionProduction of chemokinesCellular mechanismsHIV-1 replicationStem cellsCellular immunotherapeutic approachesInnate immune systemVirus-infected cellsInfected targetsPluripotent stem cellsImmunotherapeutic approachesNatural killerKiller cellsCell-based therapiesT cellsReprogramming of T Cells from Human Peripheral Blood
Loh YH, Hartung O, Li H, Guo C, Sahalie JM, Manos PD, Urbach A, Heffner GC, Grskovic M, Vigneault F, Lensch MW, Park IH, Agarwal S, Church GM, Collins JJ, Irion S, Daley GQ. Reprogramming of T Cells from Human Peripheral Blood. Cell Stem Cell 2010, 7: 15-19. PMID: 20621044, PMCID: PMC2913590, DOI: 10.1016/j.stem.2010.06.004.Peer-Reviewed Original Research
2009
A Robust Approach to Identifying Tissue-Specific Gene Expression Regulatory Variants Using Personalized Human Induced Pluripotent Stem Cells
Lee JH, Park IH, Gao Y, Li JB, Li Z, Daley GQ, Zhang K, Church GM. A Robust Approach to Identifying Tissue-Specific Gene Expression Regulatory Variants Using Personalized Human Induced Pluripotent Stem Cells. PLOS Genetics 2009, 5: e1000718. PMID: 19911041, PMCID: PMC2766639, DOI: 10.1371/journal.pgen.1000718.Peer-Reviewed Original ResearchMeSH KeywordsAllelesCell DifferentiationCell LineCells, CulturedCluster AnalysisComputational BiologyDNA, ComplementaryFlow CytometryGene Expression RegulationHuman Genome ProjectHumansInduced Pluripotent Stem CellsNucleic Acid Amplification TechniquesOrgan SpecificityRegulatory Elements, TranscriptionalReproducibility of ResultsConceptsCis-regulatory variantsPluripotent stem cellsRegulatory polymorphismsGene expressionAllele-specific gene expressionIPS cellsPrimary fibroblastsCell typesAllele-specific expressionHigh-throughput sequencingStem cellsHuman iPS cellsSkin primary fibroblastsRegulatory variantsTissue-specific variantsX chromosomeDifferentiated derivativesExpression locusCell differentiationSpecific tissuesLymphoblastoid cellsDigital-RNAPadlock probesExpressionCellsCardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells
Zwi L, Caspi O, Arbel G, Huber I, Gepstein A, Park IH, Gepstein L. Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells. Circulation 2009, 120: 1513-1523. PMID: 19786631, DOI: 10.1161/circulationaha.109.868885.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsCell DifferentiationCell LineCells, CulturedFibroblastsHumansMiceMyocytes, CardiacPluripotent Stem CellsConceptsTranscription factorsHiPS cellsCardiomyocyte differentiationCardiac-specific transcription factorsInduced pluripotent stem cellsGene expression studiesHuman induced pluripotent stem cellsStem cell linesPluripotent stem cellsCardiomyocyte differentiation potentialPluripotent stem cell lineStructural geneContracting embryoid bodiesCardiomyocyte differentiation processTranslational cardiovascular researchEmbryoid bodiesExpression studiesDifferentiation systemDifferentiation processCardiovascular regenerative medicineSarcomeric proteinsDifferentiation potentialIon channelsAdult fibroblastsFunctional properties