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 regressionIdentifying an Early Neuropathological Mechanism in Schizophrenia With Brain Organoids
Kim J, Park I. Identifying an Early Neuropathological Mechanism in Schizophrenia With Brain Organoids. Biological Psychiatry 2024, 95: 608-610. PMID: 38479977, DOI: 10.1016/j.biopsych.2024.01.015.Peer-Reviewed Original Research
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 factorFemale naïve human pluripotent stem cells carry X chromosomes with Xa-like and Xi-like folding conformations
Patterson B, Yang B, Tanaka Y, Kim K, Cakir B, Xiang Y, Kim J, Wang S, Park I. Female naïve human pluripotent stem cells carry X chromosomes with Xa-like and Xi-like folding conformations. Science Advances 2023, 9: eadf2245. PMID: 37540754, PMCID: PMC10403202, DOI: 10.1126/sciadv.adf2245.Peer-Reviewed Original ResearchConceptsNaïve human pluripotent stem cellsHuman pluripotent stem cellsX-chromosome inactivationX chromosomePluripotent stem cellsStem cellsNaïve human embryonic stem cellsX chromosome stateX chromosome statusInactive X chromosomeActive X chromosomeHuman embryonic stem cellsEarly embryonic cellsEmbryonic stem cellsUnique epigenetic regulationChromatin compactionGenomic resolutionEpigenetic regulationChromosome inactivationChromosome stateSomatic cellsEmbryonic cellsChromosomesChromosome statusCellsGeneration of ventralized human thalamic organoids with thalamic reticular nucleus
Kiral F, Cakir B, Tanaka Y, Kim J, Yang W, Wehbe F, Kang Y, Zhong M, Sancer G, Lee S, Xiang Y, Park I. Generation of ventralized human thalamic organoids with thalamic reticular nucleus. Cell Stem Cell 2023, 30: 677-688.e5. PMID: 37019105, PMCID: PMC10329908, DOI: 10.1016/j.stem.2023.03.007.Peer-Reviewed Original ResearchConceptsHuman embryonic stem cellsSingle-cell RNA sequencingReceptor tyrosine protein kinaseTyrosine protein kinaseEmbryonic stem cellsDisease-associated genesLineage developmentRNA sequencingHuman brain developmentOrganoid systemsStem cellsHuman brain organoidsNeuronal functionBrain organoidsOrganoidsBrain organoid systemsDistinct nucleiBrain developmentThalamic developmentPTCHD1NucleusKinaseGenesSequencingMutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation
Sun J, Osenberg S, Irwin A, Ma L, Lee N, Xiang Y, Li F, Wan Y, Park I, Maletic-Savatic M, Ballas N. Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation. Cell Reports 2023, 42: 111942. PMID: 36640327, PMCID: PMC10857774, DOI: 10.1016/j.celrep.2022.111942.Peer-Reviewed Original ResearchConceptsMECP2 mutationsTranscriptional regulator MeCP2Rett syndromeTranscriptional landscapeTranscriptional changesDysfunctional mitochondriaHuman astrocytesAstrocyte gene expressionGene expressionMECP2 geneMolecular signaturesMutationsPost-natal maturationMaturationDevelopmental maturationBrain bioenergeticsMolecular featuresFunctional maturationStellate morphologyMature morphologyMetabolic aberrationsHuman-based modelsAstrocytesKey roleNeurodevelopmental disorders
2022
Advanced in vitro models: Microglia in action
Cakir B, Kiral F, Park I. Advanced in vitro models: Microglia in action. Neuron 2022, 110: 3444-3457. PMID: 36327894, DOI: 10.1016/j.neuron.2022.10.004.Peer-Reviewed Original ResearchA nomenclature consensus for nervous system organoids and assembloids
Pașca SP, Arlotta P, Bateup HS, Camp JG, Cappello S, Gage FH, Knoblich JA, Kriegstein AR, Lancaster MA, Ming GL, Muotri AR, Park IH, Reiner O, Song H, Studer L, Temple S, Testa G, Treutlein B, Vaccarino FM. A nomenclature consensus for nervous system organoids and assembloids. Nature 2022, 609: 907-910. PMID: 36171373, PMCID: PMC10571504, DOI: 10.1038/s41586-022-05219-6.Peer-Reviewed Original ResearchHuman 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 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
Exploration of alcohol use disorder-associated brain miRNA–mRNA regulatory networks
Lim Y, Beane-Ebel JE, Tanaka Y, Ning B, Husted CR, Henderson DC, Xiang Y, Park IH, Farrer LA, Zhang H. Exploration of alcohol use disorder-associated brain miRNA–mRNA regulatory networks. Translational Psychiatry 2021, 11: 504. PMID: 34601489, PMCID: PMC8487426, DOI: 10.1038/s41398-021-01635-w.Peer-Reviewed Original ResearchRegional 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
Genes 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 formationPathogenesisDeconstructing and reconstructing the human brain with regionally specified brain organoids
Xiang Y, Cakir B, Park IH. Deconstructing and reconstructing the human brain with regionally specified brain organoids. Seminars In Cell And Developmental Biology 2020, 111: 40-51. PMID: 32553582, DOI: 10.1016/j.semcdb.2020.05.023.Peer-Reviewed Original ResearchDysregulation 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 driverGeneration 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 ResearchImplantation 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 neuronsSynthetic Analyses of Single-Cell Transcriptomes from Multiple Brain Organoids and Fetal Brain
Tanaka Y, Cakir B, Xiang Y, Sullivan GJ, Park IH. Synthetic Analyses of Single-Cell Transcriptomes from Multiple Brain Organoids and Fetal Brain. Cell Reports 2020, 30: 1682-1689.e3. PMID: 32049002, PMCID: PMC7043376, DOI: 10.1016/j.celrep.2020.01.038.Peer-Reviewed Original Research
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