{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:24:36Z","timestamp":1790925876308,"version":"4.1.0"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Human-derived induced pluripotent stem cell (iPSC) models of brain promise to advance our understanding of neurotoxic consequences of drug use. However, how well these models recapitulate the actual genomic landscape and cell function, as well as the drug-induced alterations, remains to be established. New\n                      <jats:italic>in vitro<\/jats:italic>\n                      models of drug exposure are needed to advance our understanding of how to protect or reverse molecular changes related to substance use disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We engineered a novel induced pluripotent stem cell-derived model of neural progenitor cells and neurons from cultured postmortem human skin fibroblasts, and directly compared these to isogenic brain tissue from the donor source. We assessed the maturity of the cell models across differentiation from stem cells to neurons using RNA cell type and maturity deconvolution analyses as well as DNA methylation epigenetic clocks trained on adult and fetal human tissue. As proof-of-concept of this model\u2019s utility for substance use disorder studies, we compared morphine- and cocaine-treated neurons to gene expression signatures in postmortem Opioid Use Disorder (OUD) and Cocaine Use Disorder (CUD) brains, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Within each human subject (N = 2, 2 clones each), brain frontal cortex epigenetic age parallels that of skin fibroblasts and closely approximates the donor\u2019s chronological age; stem cell induction from fibroblast cells effectively sets the epigenetic clock to an embryonic age; and differentiation of stem cells to neural progenitor cells and then to neurons progressively matures the cells\n                      <jats:italic>via<\/jats:italic>\n                      DNA methylation and RNA gene expression readouts. In neurons derived from an individual who died of opioid overdose, morphine treatment induced alterations in gene expression similar to those previously observed in OUD\n                      <jats:italic>ex-vivo<\/jats:italic>\n                      brain tissue, including differential expression of the immediate early gene EGR1, which is known to be dysregulated by opioid use.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In summary, we introduce an iPSC model generated from human postmortem fibroblasts that can be directly compared to corresponding isogenic brain tissue and can be used to model perturbagen exposure such as that seen in opioid use disorder. Future studies with this and other postmortem-derived brain cellular models, including cerebral organoids, can be an invaluable tool for understanding mechanisms of drug-induced brain alterations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2023.1070556","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T01:37:21Z","timestamp":1676511441000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["A human stem cell-derived neuronal model of morphine exposure reflects brain dysregulation in opioid use disorder: Transcriptomic and epigenetic characterization of postmortem-derived iPSC neurons"],"prefix":"10.3389","volume":"14","author":[{"given":"Emily F.","family":"Mendez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra L.","family":"Grimm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Stertz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Gorski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai V.","family":"Movva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Najera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Moriel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel R.","family":"Fries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Coarfa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consuelo","family":"Walss-Bass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cells"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/cr.2012.175","article-title":"Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective","volume":"23","author":"Liang","year":"2013","journal-title":"Cell Res"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/J.MCN.2015.11.009","article-title":"Transcriptomics analysis of iPSC-derived neurons and modeling of neuropsychiatric disorders","volume":"73","author":"Lin","year":"2016","journal-title":"Mol Cell Neurosci"},{"key":"ref4","first-page":"1265","article-title":"Advances in reprogramming-based study of neurologic disorders","volume-title":"Stem Cells Dev.","author":"Nityanandam","year":"2015"},{"key":"ref5","first-page":"189","article-title":"iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders","volume-title":"Cell Stem Cell","author":"Okano","year":"2022"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1186\/s13148-021-01158-7","article-title":"Cellular reprogramming and epigenetic rejuvenation. Clinical","volume":"13","author":"Simpson","year":"2021","journal-title":"Epigenetics"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14266-z","article-title":"Dissecting transcriptomic signatures of neuronal differentiation and maturation using iPSCs. Nature","volume":"11","author":"Burke","year":"2020","journal-title":"Nature Commun"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/S41576-018-0004-3","article-title":"DNA methylation-based biomarkers and the epigenetic clock theory of ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat Rev Genet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/S13148-020-00905-6","article-title":"Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden. Clinical","volume":"12","author":"Hillary","year":"2020","journal-title":"Epigenetics"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"R115","DOI":"10.1186\/GB-2013-14-10-R115","article-title":"DNA methylation age of human tissues and cell types","volume":"14","author":"Horvath","year":"2013","journal-title":"Genome Biol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"573","DOI":"10.18632\/AGING.101414","article-title":"An epigenetic biomarker of aging for lifespan and healthspan","volume":"10","author":"Levine","year":"2018","journal-title":"Aging"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"303","DOI":"10.18632\/aging.101684","article-title":"DNA methylation GrimAge strongly predicts lifespan and healthspan","volume":"11","author":"Lu","year":"2019","journal-title":"Age"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"5895","DOI":"10.18632\/aging.102173","article-title":"DNA methylation-based estimator of telomere length","volume":"11","author":"Lu","year":"2019","journal-title":"Age"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"6082","DOI":"10.1126\/sciadv.abg6082","article-title":"Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging","volume":"7","author":"Kerepesi","year":"2021","journal-title":"Sci Adv"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/S13059-016-1068-Z","article-title":"An epigenetic clock for gestational age at birth based on blood methylation data","volume":"17","author":"Knight","year":"2016","journal-title":"Genome Biol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"4238","DOI":"10.18632\/AGING.102049","article-title":"Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels","volume":"11","author":"Lee","year":"2019","journal-title":"Aging"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1186\/S13041-021-00810-W","article-title":"Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons. Molecular","volume":"14","author":"Steg","year":"2021","journal-title":"Brain"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"3619","DOI":"10.1016\/J.CELREP.2018.08.080","article-title":"Single-cell RNA-Seq uncovers a robust transcriptional response to morphine by glia","volume":"24","author":"Avey","year":"2018","journal-title":"Cell Rep"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1093\/IJNP\/PYAB043","article-title":"Genome-wide correlation of DNA methylation and gene expression in postmortem brain tissues of opioid use disorder patients","volume":"24","author":"Liu","year":"2021","journal-title":"Int J Neuropsychopharmacol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"7803","DOI":"10.1038\/S41380-021-01259-Y","article-title":"Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem human brain","volume":"26","author":"Mendez","year":"2021","journal-title":"Mol Psychiatry"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/J.BIOPSYCH.2021.06.007","article-title":"Transcriptional alterations in dorsolateral prefrontal cortex and nucleus Accumbens implicate Neuroinflammation and synaptic remodeling in opioid use disorder","volume":"90","author":"Seney","year":"2021","journal-title":"Biol Psychiatry"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"23.424239","DOI":"10.1101\/2020.12.23.424239","article-title":"Differential expression of NPAS4 in the dorsolateral prefrontal cortex following acute opioid intoxication","volume":"2020","author":"Sosnowski","year":"2020","journal-title":"BioRxiv"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"5624","DOI":"10.2174\/092986712803988893","article-title":"Side effects of cocaine abuse: multiorgan toxicity and pathological consequences","volume":"19","author":"Riezzo","year":"2012","journal-title":"Curr Med Chem"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.neuroscience.2013.05.035","article-title":"Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents","volume":"247","author":"\u00c1lvaro-Bartolom\u00e9","year":"2013","journal-title":"Neuroscience"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e12719","DOI":"10.1111\/adb.12719","article-title":"Cocaine\u2019omics: genome-wide and transcriptome-wide analyses provide biological insight into cocaine use and dependence","volume":"25","author":"Huggett","year":"2020","journal-title":"Addict Biol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"5412","DOI":"10.1038\/s41598-017-05720-3","article-title":"Gene network dysregulation in dorsolateral prefrontal cortex neurons of humans with cocaine use disorder","volume":"7","author":"Ribeiro","year":"2017","journal-title":"Sci Rep"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1038\/s41598-018-38209-8","article-title":"Differentially expressed gene networks, biomarkers, long noncoding RNAs, and shared responses with cocaine identified in the midbrains of human opioid abusers","volume":"9","author":"Saad","year":"2019","journal-title":"Sci Rep"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/S10561-008-9077-0\/FIGURES\/1","article-title":"Brain banks: benefits, limitations and cautions concerning the use of post-mortem brain tissue for molecular studies","volume":"9","author":"Ferrer","year":"2008","journal-title":"Cell Tissue Bank"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/J.BIOPSYCH.2010.09.035","article-title":"Novel approaches to the study of postmortem brain in psychiatric illness: old limitations and new challenges","volume":"69","author":"McCullumsmith","year":"2011","journal-title":"Biol Psychiatry"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1097\/NEN.0000000000000190","article-title":"Effects of postmortem interval on biomolecule integrity in the brain","volume":"74","author":"Nagy","year":"2015","journal-title":"J Neuropathol Exp Neurol"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"4581","DOI":"10.1111\/BPH.15228","article-title":"Induced pluripotent stem cells as a platform to understand patient-specific responses to opioids and anaesthetics","volume":"177","author":"Obal","year":"2020","journal-title":"Br J Pharmacol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e00491","DOI":"10.1002\/BRB3.491","article-title":"Using iPSC-derived human DA neurons from opioid-dependent subjects to study dopamine dynamics","volume":"6","author":"Sheng","year":"2016","journal-title":"Brain Behav"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1038\/S41380-019-0507-0","article-title":"Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons","volume":"25","author":"Halikere","year":"2020","journal-title":"Mol Psychiatry"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"102065","DOI":"10.1016\/J.SCR.2020.102065","article-title":"Methadone interrupts neural growth and function in human cortical organoids","volume":"49","author":"Yao","year":"2020","journal-title":"Stem Cell Res"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/J.SLASD.2022.01.003","article-title":"A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids","volume":"27","author":"Boutin","year":"2022","journal-title":"SLAS Discovery"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"04.490442","DOI":"10.1101\/2022.05.04.490442","article-title":"Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening","volume":"2022","author":"Strong","year":"2022","journal-title":"BioRxiv"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"467","DOI":"10.3390\/PHARMACEUTICS11090467","article-title":"Brain delivery of a potent opioid receptor agonist, Biphalin during ischemic stroke: role of organic anion transporting polypeptide (OATP)","volume":"11","author":"Albekairi","year":"2019","journal-title":"Pharmaceutics"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12987-020-00200-9\/FIGURES\/6","article-title":"Advances in blood-brain barrier modeling in microphysiological systems highlight critical differences in opioid transport due to cortisol exposure","volume":"17","author":"Brown","year":"2020","journal-title":"Fluids and Barriers of the CNS"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.1016\/J.JACEP.2020.08.034","article-title":"Rapid assessment of Proarrhythmic potential using human iPSC-derived cardiomyocytes","volume":"6","author":"Geiger","year":"2020","journal-title":"Clinical Electrophysiol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"13.22273746","DOI":"10.1101\/2022.04.13.22273746","article-title":"The UT health psychological autopsy interview schedule (UTH- PAIS) \u2013 description and reliability of diagnoses and Transdiagnostic personality measures","volume":"2022","author":"Meyer","year":"2022","journal-title":"MedRxiv"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/s41386-020-00924-0","article-title":"Convergent genomic and pharmacological evidence of PI3K\/GSK3 signaling alterations in neurons from schizophrenia patients","volume":"46","author":"Stertz","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/BIOINFORMATICS\/BTT656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref44","volume-title":"R: A language and environment for statistical computing","year":"2022"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1093\/BIOINFORMATICS\/BTU049","article-title":"Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/S13742-015-0047-8\/2707533","article-title":"Second-generation PLINK: rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"GigaScience"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2987","DOI":"10.1093\/BIOINFORMATICS\/BTR509","article-title":"A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data","volume":"27","author":"Li","year":"2011","journal-title":"Bioinformatics"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/BIOINFORMATICS\/BTP352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1038\/ng.3656","article-title":"Next-generation genotype imputation service and methods","volume":"48","author":"Das","year":"2016","journal-title":"Nat Genet"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"563866","DOI":"10.1101\/563866","article-title":"Sequencing of 53,831 diverse genomes from the NHLBI TOPMed program","volume":"2","author":"Taliun","year":"2019","journal-title":"BioRxiv"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1093\/BIOINFORMATICS\/BTU704","article-title":"minimac2: faster genotype imputation","volume":"31","author":"Fuchsberger","year":"2015","journal-title":"Bioinformatics"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"4288","DOI":"10.1093\/nar\/gks042","article-title":"Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation","volume":"40","author":"McCarthy","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12859-016-1323-Z\/FIGURES\/5","article-title":"variancePartition: interpreting drivers of variation in complex gene expression studies","volume":"17","author":"Hoffman","year":"2016","journal-title":"BMC Bioinfo"},{"key":"ref55","author":"Alexa","year":"2020"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1007\/s11336-013-9328-2","article-title":"A nondegenerate penalized likelihood estimator for variance parameters in multilevel models","volume":"78","author":"Chung","year":"2013","journal-title":"Psychometrika"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1111\/ggi.13500","article-title":"Changes in telomere length with aging in human neurons and glial cells revealed by quantitative fluorescence in situ hybridization analysis","volume":"18","author":"Tomita","year":"2018","journal-title":"Geriatr Gerontol Int"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1111\/J.1365-2443.2012.01595.X","article-title":"Epigenetic rejuvenation","volume":"17","author":"Manukyan","year":"2012","journal-title":"Genes Cells"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41580-019-0204-5","article-title":"The ageing epigenome and its rejuvenation","volume":"21","author":"Zhang","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref60","article-title":"Substance-related and addictive disorders","volume-title":"Diagnostic and Statistical Manual of Mental Disorders. 5th Edn","year":"2022"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"79","DOI":"10.3389\/fnbeh.2018.00079","article-title":"Immediate early genes, memory and psychiatric disorders: focus on c-Fos, Egr1 and arc","volume":"12","author":"Gallo","year":"2018","journal-title":"Front Behav Neurosci"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/978-3-540-74805-2_8\/COVER","article-title":"Presynaptic signaling by heterotrimeric G-proteins","volume":"184","author":"Brown","year":"2008","journal-title":"Handb Exp Pharmacol"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1038\/nature08797","article-title":"Direct conversion of fibroblasts to functional neurons by defined factors","volume":"463","author":"Vierbuchen","year":"2010","journal-title":"Nature"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1146\/ANNUREV-GENET-120417-031534","article-title":"Aging in a dish: iPSC-derived and directly induced neurons for studying brain aging and age-related neurodegenerative diseases","volume":"52","author":"Mertens","year":"2018","journal-title":"Annu Rev Genet"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/S13024-018-0258-4","article-title":"2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling","volume":"13","author":"Centeno","year":"2018","journal-title":"Molecular Neurodegeneration"},{"key":"ref67","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.1247125\/ASSET\/D8794BAA-40A0-43FF-901B-011021094BBA\/ASSETS\/GRAPHIC\/345_1247125_F4.JPEG","article-title":"Organogenesisin a dish: modeling development and disease using organoid technologies","volume":"345","author":"Lancaster","year":"2014","journal-title":"Science"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2023.1070556\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T01:37:30Z","timestamp":1676511450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2023.1070556\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":67,"alternative-id":["10.3389\/fpsyt.2023.1070556"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2023.1070556","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,16]]},"article-number":"1070556"}}