2025
Early developmental origins of cortical disorders modeled in human neural stem cells
Mato-Blanco X, Kim S, Jourdon A, Ma S, Choi S, Giani A, Paredes M, Tebbenkamp A, Liu F, Duque A, Vaccarino F, Sestan N, Colantuoni C, Rakic P, Santpere G, Micali N. Early developmental origins of cortical disorders modeled in human neural stem cells. Nature Communications 2025, 16: 6347. PMID: 40634286, PMCID: PMC12241556, DOI: 10.1038/s41467-025-61316-w.Peer-Reviewed Original ResearchConceptsSingle-cell transcriptomicsNeural stem cellsNeural stem cell lineage commitmentGene regulatory networksEarly developmental originHuman neural stem cellsRegulatory networksExpression dynamicsRisk genesStem cellsCortical disordersTransition in vitroTelencephalic developmentEarly phaseGene dysfunctionLineage commitmentCell trajectoriesHuman corticogenesisHuman brain dysfunctionGenesNSCs in vitroMultiple diseasesIn vivoBrain dysfunctionCorticogenesisti-scMR: trajectory-inference-based dynamic single-cell Mendelian randomization identifies causal genes underlying phenotypic differences
Sun J, Dong Q, Wei J, Gao Y, Yu Z, Hu X, Zhang Y. ti-scMR: trajectory-inference-based dynamic single-cell Mendelian randomization identifies causal genes underlying phenotypic differences. NAR Genomics And Bioinformatics 2025, 7: lqaf082. PMID: 40630931, PMCID: PMC12231591, DOI: 10.1093/nargab/lqaf082.Peer-Reviewed Original ResearchConceptsMendelian randomizationCausal genesSingle-cell expressionGenetic instrumental variablesPhenotypic differencesIndividual phenotypesPotential causal genesPresence of confoundersEffects of gene expressionGenotype to phenotypeCausal pathwaysSingle-cell datasetsDifferential expression analysisExpression of genesPopulation genomicsSingle-cell transcriptomicsComplex traitsPopulation geneticsTrait lociImmune cell differentiationTranscriptomic landscapeTrajectory inferenceTranscriptional featuresInstrumental variablesCellular developmentCell type and cell signalling innovations underlying mammalian pregnancy
Stadtmauer D, Basanta S, Maziarz J, Cole A, Dagdas G, Smith G, van Breukelen F, Pavličev M, Wagner G. Cell type and cell signalling innovations underlying mammalian pregnancy. Nature Ecology & Evolution 2025, 9: 1469-1486. PMID: 40596730, PMCID: PMC12328210, DOI: 10.1038/s41559-025-02748-x.Peer-Reviewed Original ResearchConceptsCell typesDecidual cellsSingle-cell transcriptomicsLigand-receptor pairsMammalian ancestorMammal diversitySignaling networksFetal-maternal interfaceMaternal decidual cellsCell signalingMaternal cell typesExclusive expressionRace dynamicsEvolutionary puzzleMammalian placentationTranscriptomic signaturesFetal trophoblastHuman deciduaMaternal stromaMammalian pregnancyInvasive trophoblastCo-evolutionHaemochorial placentationTenrecsSignal innovationA deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases
Zheng Y, Schupp J, Adams T, Clair G, Justet A, Ahangari F, Yan X, Hansen P, Carlon M, Cortesi E, Vermant M, Vos R, De Sadeleer L, Rosas I, Pineda R, Sembrat J, Königshoff M, McDonough J, Vanaudenaerde B, Wuyts W, Kaminski N, Ding J. A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases. Nature Biomedical Engineering 2025, 1-26. PMID: 40542107, DOI: 10.1038/s41551-025-01423-7.Peer-Reviewed Original ResearchComplex cellular dynamicsCellular dynamicsSingle-cell transcriptomic dataIn silico drug discoverySingle-cell transcriptomicsTranscriptome dataPotential therapeutic drug candidateComplex diseasesHuman diseasesIdiopathic pulmonary fibrosisTherapeutic drug candidateCell embeddingDrug discoveryPulmonary fibrosisDrug candidatesDisease progressionHuman tissuesHuman precision-cut lung slicesDynamic analysisPrecision-cut lung slicesPathological landscapeComputational toolsAnti-fibrotic effectsUnagiTranscriptomeSingle-cell elderly blood–CSF atlas implicates peripherally influenced immune dysregulation in normal pressure hydrocephalus
Duy P, Kiziltug E, Greenberg A, Mehta N, Hao L, Fortes C, Mullany S, Fan B, Manichaikul A, Teich A, Chan D, Alper S, Hyman B, Arnold S, McKhann G, Frosch M, Kahle K. Single-cell elderly blood–CSF atlas implicates peripherally influenced immune dysregulation in normal pressure hydrocephalus. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2412159122. PMID: 40324076, PMCID: PMC12087963, DOI: 10.1073/pnas.2412159122.Peer-Reviewed Original ResearchConceptsIdiopathic normal pressure hydrocephalusNormal pressure hydrocephalusImmune dysregulationPeripheral bloodPressure hydrocephalusIdiopathic normal pressure hydrocephalus patientsProinflammatory alterationsVentricular CSFSingle-cell transcriptomicsINPH patientsCell populationsPatientsNeuroglial cellsCSFBloodHydrocephalusBaseline cognitive functionCognitive functionDysregulationMonocytesSpecification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines
Scuderi S, Kang T, Jourdon A, Nelson A, Yang L, Wu F, Anderson G, Mariani J, Tomasini L, Sarangi V, Abyzov A, Levchenko A, Vaccarino F. Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines. Cell Stem Cell 2025, 32: 970-989.e11. PMID: 40315847, PMCID: PMC12145255, DOI: 10.1016/j.stem.2025.04.006.Peer-Reviewed Original ResearchConceptsGradient of WntGene expression programsSingle-cell transcriptomicsBrain lineagesMorphogen gradientsEpigenetic variationDorso-ventral axisShh signalingExpression programsMorphogenFetal human brainHuman iPSC linesPluripotent stem cellsCell linesNeuronal lineageNeural tubeShhWntLineagesLine-to-line variationEarly patterningPattern systemPattern variationHuman brain regionsIPSC linesRecessive genetic contribution to congenital heart disease in 5,424 probands
Dong W, Jin S, Sierant M, Lu Z, Li B, Lu Q, Morton S, Zhang J, López-Giráldez F, Nelson-Williams C, Knight J, Zhao H, Cao J, Mane S, Gruber P, Lek M, Goldmuntz E, Deanfield J, Giardini A, Mital S, Russell M, Gaynor J, Cnota J, Wagner M, Srivastava D, Bernstein D, Porter G, Newburger J, Roberts A, Yandell M, Yost H, Tristani-Firouzi M, Kim R, Seidman J, Chung W, Gelb B, Seidman C, Lifton R, Brueckner M. Recessive genetic contribution to congenital heart disease in 5,424 probands. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2419992122. PMID: 40030011, PMCID: PMC11912448, DOI: 10.1073/pnas.2419992122.Peer-Reviewed Original ResearchConceptsRecessive genotypeCHD probandsCongenital heart diseaseAssociated with laterality defectsGene-based analysisAnalyzed whole-exome sequencingLeft-sided congenital heart diseaseWhole-exome sequencingCongenital heart disease phenotypeAshkenazi Jewish probandsOffspring of consanguineous unionsSingle-cell transcriptomicsCHD geneExome sequencingMouse notochordSecreted proteinsConsanguineous familyFounder variantGenesSignificant enrichmentLaterality phenotypesHeart diseaseProbandsAbnormal contractile functionConsanguineous unionsBiological and clinical significance of tumour-infiltrating lymphocytes in the era of immunotherapy: a multidimensional approach
Lopez de Rodas M, Villalba-Esparza M, Sanmamed M, Chen L, Rimm D, Schalper K. Biological and clinical significance of tumour-infiltrating lymphocytes in the era of immunotherapy: a multidimensional approach. Nature Reviews Clinical Oncology 2025, 22: 163-181. PMID: 39820025, DOI: 10.1038/s41571-024-00984-x.Peer-Reviewed Original ResearchConceptsTumor-infiltrating lymphocytesImmune-checkpoint inhibitorsTumor-infiltrating lymphocyte subpopulationsClinical significance of tumor-infiltrating lymphocytesPredictive value of tumor-infiltrating lymphocytesSignificance of tumor-infiltrating lymphocytesStudy of tumor-infiltrating lymphocytesImmune-checkpoint inhibitor therapyImmune-mediated tumor eliminationEra of immunotherapyT cell dysfunctionBiomarkers of responseSolid tumor typesImmunotherapeutic approachesAntigen-reactiveTumor microenvironmentTumor typesClinical outcomesTumor eliminationClinical significanceSingle-cell transcriptomicsPredictive valueAnticancer mechanismClinical implicationsResistance mechanisms
2024
Single-Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis.
Zhao A, Unterman A, Abu Hussein N, Sharma P, Nikola F, Flint J, Yan X, Adams T, Justet A, Sumida T, Zhao J, Schupp J, Raredon M, Ahangari F, Deluliis G, Zhang Y, Buendia-Roldan I, Adegunsoye A, Sperling A, Prasse A, Ryu C, Herzog E, Selman M, Pardo A, Kaminski N. Single-Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis. American Journal Of Respiratory And Critical Care Medicine 2024, 210: 1252-1266. PMID: 38924775, PMCID: PMC11568434, DOI: 10.1164/rccm.202401-0078oc.Peer-Reviewed Original ResearchFibrotic hypersensitivity pneumonitisIdiopathic pulmonary fibrosisPeripheral blood mononuclear cellsBronchoalveolar lavage cellsBlood mononuclear cellsClassical monocytesHypersensitivity pneumonitisPulmonary fibrosisT cellsImmune perturbationsLavage cellsMononuclear cellsCD8+ T cellsCytotoxic T cellsInterstitial lung diseaseHypersensitivity pneumonitis patientsCytotoxic CD4Immune aberrationsPneumonic patientsPneumonitisLung diseaseHealthy controlsImmune mechanismsPatient cellsSingle-cell transcriptomicsPerivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy.
Choudhury A, Cady M, Lucas C, Najem H, Phillips J, Palikuqi B, Zakimi N, Joseph T, Birrueta J, Chen W, Oberheim Bush N, Hervey-Jumper S, Klein O, Toedebusch C, Horbinski C, Magill S, Bhaduri A, Perry A, Dickinson P, Heimberger A, Ashworth A, Crouch E, Raleigh D. Perivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy. Cancer Discovery 2024, 14: 1823-1837. PMID: 38742767, PMCID: PMC11452293, DOI: 10.1158/2159-8290.cd-23-1459.Peer-Reviewed Original ResearchConceptsResistance to radiotherapyMeningioma tumorigenesisSystemic therapyTreating meningiomasStem cellsGenetically engineered mouse modelsTumor-initiating capacityHigh-grade meningiomasReduced tumor growthPrimary intracranial tumorsMeningioma growthImproved survivalIntracranial tumorsRadiotherapyTherapeutic vulnerabilitiesTumor growthMeningiomasMouse modelSingle-cell transcriptomicsLineage tracingNotch3TumorigenesisCell proliferationReduced survivalCell typesNKX2-2 based nuclei sorting on frozen human archival pancreas enables the enrichment of islet endocrine populations for single-nucleus RNA sequencing
Xie G, Toledo M, Hu X, Yong H, Sanchez P, Liu C, Naji A, Irianto J, Wang Y. NKX2-2 based nuclei sorting on frozen human archival pancreas enables the enrichment of islet endocrine populations for single-nucleus RNA sequencing. BMC Genomics 2024, 25: 427. PMID: 38689254, PMCID: PMC11059690, DOI: 10.1186/s12864-024-10335-w.Peer-Reviewed Original ResearchConceptsSingle-nucleus RNA sequencingRNA sequencingNuclei sortingSnRNA-seqGene expressionEndocrine populationsFluorescence-activated nuclei sortingHuman isletsGene expression librariesNuclei isolation protocolSingle-cell RNA sequencingFrozen archival tissuesIsolated human isletsHuman pancreatic endocrine cellsSingle-cell transcriptomicsTranscriptomic studiesCytoplasmic contaminationTranscriptome profilingConclusionsOur workNKX2-2Isolated nucleiRNA integrityLiving cellsIsolation protocolPancreatic endocrine cells
2023
Single-cell reconstruction and mutation enrichment analysis identifies dysregulated cardiomyocyte and endothelial cells in congenital heart disease
Tambi R, Zehra B, Nandkishore S, Sharafat S, Kader F, Nassir N, Mohamed N, Ahmed A, Abdel Hameid R, Alasrawi S, Brueckner M, Kuebler W, Chung W, Alsheikh-Ali A, Di Donato R, Uddin M, Berdiev B. Single-cell reconstruction and mutation enrichment analysis identifies dysregulated cardiomyocyte and endothelial cells in congenital heart disease. Physiological Genomics 2023, 55: 634-646. PMID: 37811720, PMCID: PMC11550899, DOI: 10.1152/physiolgenomics.00070.2023.Peer-Reviewed Original ResearchConceptsSingle-cell transcriptomesCHD genesRisk genesEndocardial cellsMultiple genesCell typesSingle-cell transcriptomicsPhenotypic heterogeneityDe novo variantsCongential heart diseaseSingle-cell reconstructionGenesReconstruction analysisNeonatal congenital anomaliesGene heterogeneityAnalysis identifiesTranscriptomeMissense variantsNovo variantsCongenital heart diseaseGenomicsHeterogenous expressionFunction variantsHeart diseaseGenetics guidelinesModeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis
Jourdon A, Wu F, Mariani J, Capauto D, Norton S, Tomasini L, Amiri A, Suvakov M, Schreiner J, Jang Y, Panda A, Nguyen C, Cummings E, Han G, Powell K, Szekely A, McPartland J, Pelphrey K, Chawarska K, Ventola P, Abyzov A, Vaccarino F. Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis. Nature Neuroscience 2023, 26: 1505-1515. PMID: 37563294, PMCID: PMC10573709, DOI: 10.1038/s41593-023-01399-0.Peer-Reviewed Original ResearchConceptsIdiopathic autism spectrum disorderCortical neuron subtypesAutism spectrum disorderEarly cortical developmentCortical organoidsCortical plateExcitatory neuronsCortical developmentRare formNeuron subtypesUnaffected fatherASD pathogenesisForebrain organoidsEarly neurogenesisRare variantsIdiopathic autismRisk genesTranscriptomic alterationsNeuronsProbandsSingle-cell transcriptomicsForebrain developmentSpectrum disorderTranscriptomic changesAlterationsSelf-patterning of human stem cells into post-implantation lineages
Pedroza M, Gassaloglu S, Dias N, Zhong L, Hou T, Kretzmer H, Smith Z, Sozen B. Self-patterning of human stem cells into post-implantation lineages. Nature 2023, 622: 574-583. PMID: 37369348, PMCID: PMC10584676, DOI: 10.1038/s41586-023-06354-4.Peer-Reviewed Original ResearchConceptsStem cellsPlacental cell typesPost-implantation embryonic developmentHuman pluripotent stem cellsPluripotent stem cellsHuman embryonic developmentEmbryonic developmentHuman stem cellsCongenital pathologyPost-implantation epiblastDiverse cell statesSingle-cell transcriptomicsAmniotic ectodermExtra-embryonic endodermSpontaneous differentiationSignaling hubThree-dimensional structureSecreted modulatorsCell typesCell-matrix interactions control biliary organoid polarity, architecture, and differentiation
Fiorotto R, Mariotti V, Taleb S, Zehra S, Nguyen M, Amenduni M, Strazzabosco M. Cell-matrix interactions control biliary organoid polarity, architecture, and differentiation. Hepatology Communications 2023, 7: e0094. PMID: 36972396, PMCID: PMC10503667, DOI: 10.1097/hc9.0000000000000094.Peer-Reviewed Original ResearchConceptsBiliary organoidsNovel organoid modelImmune cell typesOrganotypic culture systemProinflammatory chemokinesStem cell featuresBiliary epitheliumExtracellular matrixEpithelial permeabilityImportant causeBile acidsBiliary differentiationBile transportHuman liverOrganoid modelsDisease modelsCholangiopathyCell featuresTight junctionsLiverCell typesInternal lumenOrganoidsSingle-cell transcriptomicsPathogenic bacteriaA Flow Artist for High-Dimensional Cellular Data
MacDonald K, Bhaskar D, Thampakkul G, Nguyen N, Zhang J, Perlmutter M, Adelstein I, Krishnaswamy S. A Flow Artist for High-Dimensional Cellular Data. 2023, 00: 1-6. DOI: 10.1109/mlsp55844.2023.10285942.Peer-Reviewed Original ResearchSingle-cell transcriptomicsHigh-throughput biologyChapter 3 Single-cell transcriptomics
Marczyk M, Kujawa T, Papiez A, Polanska J. Chapter 3 Single-cell transcriptomics. 2023, 67-84. DOI: 10.1016/b978-0-323-91810-7.00015-7.ChaptersSingle-cell transcriptomicsSingle-cell technologiesCell trajectory inferenceGene expression dataSimilar cell typesTranscriptional signalsCancer cell line dataRNAseq dataGene expressionCellular heterogeneitySequencing platformsBreast cancer cell line dataExpression dataCell line dataGroups of cellsTrajectory inferenceCell typesIndividual cellsMolecular characteristicsProper processingCellsTranscriptomicsGenesExpressionCertain steps
2022
Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines
Godoy-Tena G, Barmada A, Morante-Palacios O, de la Calle-Fabregat C, Martins-Ferreira R, Ferreté-Bonastre A, Ciudad L, Ruiz-Sanmartín A, Martínez-Gallo M, Ferrer R, Ruiz-Rodriguez J, Rodríguez-Ubreva J, Vento-Tormo R, Ballestar E. Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines. Genome Medicine 2022, 14: 134. PMID: 36443794, PMCID: PMC9706884, DOI: 10.1186/s13073-022-01137-4.Peer-Reviewed Original ResearchConceptsDNA methylation alterationsSevere COVID-19 patientsInterferon-related genesCOVID-19 patientsCell typesMethylation alterationsMyeloid differentiationSingle-cell transcriptomesSingle-cell transcriptomicsDNA methylation changesGene expression changesPeripheral blood monocytesImmune cell typesMethylationEPIC BeadChip arraySpecific DNA methylation alterationsTranscriptional reprogrammingDNA methylomeTranscriptomic reprogrammingDNA methylationInflammatory cytokinesMethylation changesEpigenetic alterationsBlood monocytesExpression changesBeadChip arrayExpression 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
Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis
Zhang X, McDonald JG, Aryal B, Canfrán-Duque A, Goldberg EL, Araldi E, Ding W, Fan Y, Thompson BM, Singh AK, Li Q, Tellides G, Ordovás-Montanes J, García Milian R, Dixit VD, Ikonen E, Suárez Y, Fernández-Hernando C. Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2107682118. PMID: 34782454, PMCID: PMC8617522, DOI: 10.1073/pnas.2107682118.Peer-Reviewed Original ResearchConceptsCholesterol biosynthetic intermediatesBiosynthetic intermediatesDependent inflammasome activationSingle-cell transcriptomicsMitochondrial reactive oxygen species productionFoam cell formationMacrophage foam cellsReactive oxygen species productionHuman coronary artery lesionsConversion of desmosterolTranscriptomic analysisMacrophage cholesterol metabolismPhysiological contextOxygen species productionLiver X receptor ligandsApoptosis-associated speck-like proteinRetinoid X receptor activationX receptor ligandsInflammasome activationAtherosclerotic plaquesSpeck-like proteinCholesterol homeostasisMacrophage inflammasome activationKey moleculesCell formation
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