{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:33:07Z","timestamp":1791387187792,"version":"4.3.3"},"reference-count":67,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R0AG1061069 and R01AG061901"],"award-info":[{"award-number":["R0AG1061069 and R01AG061901"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["AZ160082"],"award-info":[{"award-number":["AZ160082"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["Zenith award"],"award-info":[{"award-number":["Zenith award"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Traumatic brain injury (TBI) is a head injury that disrupts the normal brain structure and function. TBI has been extensively studied using various in vitro and in vivo models. Most of the studies have been done with rodent models, which may respond differently to TBI than human nerve cells. Taking advantage of the recent development of cerebral organoids (COs) derived from human induced pluripotent stem cells (iPSCs), which resemble the architecture of specific human brain regions, here, we adapted the controlled cortical impact (CCI) model to induce TBI in human COs as a novel in vitro platform. To adapt the CCI procedure into COs, we have developed a phantom brain matrix, matching the mechanical characteristics of the brain, altogether with an empty mouse skull as a platform to allow the use of the stereotactic CCI equipment on COs. After the CCI procedure, COs were histologically prepared to evaluate neurons and astrocyte populations using the microtubule-associated protein 2 (MAP2) and the glial fibrillary acidic protein (GFAP). Moreover, a marker of metabolic response, the neuron-specific enolase (NSE), and cellular death using cleaved caspase 3 were also analyzed. Our results show that human COs recapitulate the primary pathological changes of TBI, including metabolic alterations related to neuronal damage, neuronal loss, and astrogliosis. This novel approach using human COs to model TBI in vitro holds great potential and opens new alternatives for understanding brain abnormalities produced by TBI, and for the development and testing of new therapeutic approaches.<\/jats:p>","DOI":"10.3390\/cells10102683","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T09:24:04Z","timestamp":1633598644000},"page":"2683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Modeling Traumatic Brain Injury in Human Cerebral Organoids"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7335-3005","authenticated-orcid":false,"given":"Santiago","family":"Ramirez","sequence":"first","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhisek","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Sepulveda","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Becerra-Calixto","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7565-5138","authenticated-orcid":false,"given":"Nicolas","family":"Bravo-Vasquez","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Gherardelli","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Chavez","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Soto","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.4103\/0253-7176.203129","article-title":"Traumatic brain injury and neuropsychiatric complications","volume":"39","author":"Ahmed","year":"2017","journal-title":"Indian J. Psychol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.mcn.2015.03.001","article-title":"Epidemiology of mild traumatic brain injury and neurodegenerative disease","volume":"66","author":"Gardner","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"CDC (2019). Brain Injury Awareness Month March 2019. MMWR Morb Mortal Wkly Rep., 68, 237.","DOI":"10.15585\/mmwr.mm6810a1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"341","DOI":"10.3233\/NRE-2007-22502","article-title":"The impact of traumatic brain injuries: A global perspective","volume":"22","author":"Hyder","year":"2007","journal-title":"NeuroRehabilitation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/bph.13125","article-title":"The contribution of astrocytes and microglia to traumatic brain injury","volume":"173","author":"Karve","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/bja\/aem131","article-title":"Pathophysiology of traumatic brain injury","volume":"99","author":"Werner","year":"2007","journal-title":"Br. J. Anaesth."},{"key":"ref_7","unstructured":"Krishnamurthy, K., and Laskowitz, D.T. (2016). Cellular and molecular mechanisms of secondary neuronal injury following traumatic brain injury. Translational Research in Traumatic Brain Injury, CRC Press\/Taylor and Francis Group."},{"key":"ref_8","first-page":"134ra60","article-title":"Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model","volume":"4","author":"Goldstein","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1212\/WNL.54.6.1316","article-title":"Head injury and the risk of AD in the MIRAGE study","volume":"54","author":"Guo","year":"2000","journal-title":"Neurology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/bpa.12248","article-title":"The Neuropathology of Chronic Traumatic Encephalopathy","volume":"25","author":"McKee","year":"2015","journal-title":"Brain Pathol."},{"key":"ref_11","first-page":"222","article-title":"Pathophysiology of traumatic brain injury","volume":"18","author":"Mustafa","year":"2013","journal-title":"Neurosciences"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Osier, N., and Dixon, C.E. (2017). Mini review of controlled cortical impact: A well-suited device for concussion research. Brain Sci., 7.","DOI":"10.3390\/brainsci7070088"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41586-019-1506-7","article-title":"Conserved cell types with divergent features in human versus mouse cortex","volume":"573","author":"Hodge","year":"2019","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nrn3407","article-title":"Animal models of traumatic brain injury","volume":"14","author":"Xiong","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.scr.2018.09.006","article-title":"Rapid and efficient differentiation of functional motor neurons from human iPSC for neural injury modelling","volume":"32","author":"Bianchi","year":"2018","journal-title":"Stem Cell Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev-bioeng-071910-124706","article-title":"In vitro models of traumatic brain injury","volume":"15","author":"Morrison","year":"2011","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"34097","DOI":"10.1038\/srep34097","article-title":"Stretch Injury of Human Induced Pluripotent Stem Cell Derived Neurons in a 96 Well Format","volume":"6","author":"Sherman","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1038\/s41593-020-00730-3","article-title":"Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo","volume":"23","author":"Chiaradia","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cobme.2020.05.004","article-title":"Modeling traumatic brain injury with human brain organoids","volume":"14","author":"Jgamadze","year":"2020","journal-title":"Curr. Opin. Biomed. Eng."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.cell.2016.04.032","article-title":"Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure","volume":"165","author":"Qian","year":"2016","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20284","DOI":"10.1073\/pnas.1315710110","article-title":"Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex","volume":"110","author":"Kadoshima","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","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":"ref_23","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s41586-019-1289-x","article-title":"Individual brain organoids reproducibly form cell diversity of the human cerebral cortex","volume":"570","author":"Velasco","year":"2019","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15672","DOI":"10.1073\/pnas.1520760112","article-title":"Human cerebral organoids recapitulate gene expression programs of fetal neocortex development","volume":"112","author":"Camp","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.1016\/j.celrep.2016.12.001","article-title":"Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain","volume":"17","author":"Luo","year":"2016","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.devcel.2016.02.023","article-title":"Vascular Influence on Ventral Telencephalic Progenitors and Neocortical Interneuron Production","volume":"36","author":"Tan","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.cell.2019.01.017","article-title":"Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution","volume":"176","author":"Pollen","year":"2019","journal-title":"Cell"},{"key":"ref_28","first-page":"816","article-title":"Zika virus: Zika virus impairs growth in human neurospheres and brain organoids","volume":"352","author":"Garcez","year":"2016","journal-title":"Science 80"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cell.2015.06.034","article-title":"FOXG1-Dependent Dysregulation of GABA\/Glutamate Neuron Differentiation in Autism Spectrum Disorders","volume":"162","author":"Mariani","year":"2015","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1038\/s41380-018-0229-8","article-title":"Modeling amyloid beta and tau pathology in human cerebral organoids","volume":"23","author":"Gonzalez","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.neuron.2018.05.008","article-title":"APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer\u2019s Disease Phenotypes in Human iPSC-Derived Brain Cell Types","volume":"98","author":"Lin","year":"2018","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Raja, W.K., Mungenast, A.E., Lin, Y.T., Ko, T., Abdurrob, F., Seo, J., and Tsai, L.H. (2016). Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer\u2019s disease phenotypes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161969"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/neu.1988.5.1","article-title":"Controlled Cortical Impact: A New Experimental Brain Injury Model","volume":"5","author":"Lighthall","year":"1988","journal-title":"J. Neurotrauma"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1089\/neu.2018.6348","article-title":"Traumatic brain injury induces tau aggregation and spreading","volume":"37","author":"Edwards","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fneur.2016.00134","article-title":"The controlled cortical impact model: Applications, considerations for researchers, and future directions","volume":"7","author":"Osier","year":"2016","journal-title":"Front. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"118","DOI":"10.5214\/ans.0972.7531.200309","article-title":"The substitute brain and the potential of the gel model","volume":"20","author":"Pomfret","year":"2013","journal-title":"Ann. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jbiomech.2019.05.033","article-title":"Comparison of porcine brain mechanical properties to potential tissue simulant materials in quasi-static and sinusoidal compression","volume":"92","author":"Singh","year":"2019","journal-title":"J. Biomech."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.16965\/ijar.2016.181","article-title":"An alternative approach to bone cleaning methods for anatomical purposes","volume":"4","author":"Aggarwal","year":"2016","journal-title":"Int. J. Anat. Res."},{"key":"ref_39","first-page":"88","article-title":"The role of astrocytes in neuroprotection after brain stroke: Potential in cell therapy","volume":"10","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3276","DOI":"10.1523\/JNEUROSCI.4707-08.2009","article-title":"Uniquely hominid features of adult human astrocytes","volume":"29","author":"Oberheim","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-94-017-7215-0_9","article-title":"Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects","volume":"867","author":"Bottoni","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e97105","DOI":"10.1172\/jci.insight.97105","article-title":"The current state of biomarkers of mild traumatic brain injury","volume":"3","author":"Kim","year":"2018","journal-title":"JCI Insight"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.3109\/02699052.2012.694567","article-title":"Multiple indicators model of long-term mortality in traumatic brain injury","volume":"26","author":"Gradisek","year":"2012","journal-title":"Brain Inj."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s00381-018-3955-y","article-title":"Serial measurement of S100B and NSE in pediatric traumatic brain injury","volume":"35","author":"Park","year":"2019","journal-title":"Child\u2019s Nerv. Syst."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1186\/s13054-016-1450-y","article-title":"Utility of neuron-specific enolase in traumatic brain injury; relations to S100B levels, outcome, and extracranial injury severity","volume":"20","author":"Thelin","year":"2016","journal-title":"Crit. Care"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1089\/neu.2000.17.927","article-title":"Apoptosis after traumatic brain injury","volume":"10","author":"Raghupathi","year":"2000","journal-title":"J. Neurotrauma"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1046\/j.1471-4159.2000.740740.x","article-title":"Caspase-3 mediated neuronal death after traumatic brain injury in rats","volume":"74","author":"Clark","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fnana.2011.00029","article-title":"The evolution of the brain, the human nature of cortical circuits, and intellectual creativity","volume":"5","author":"Defelipe","year":"2011","journal-title":"Front. Neuroanat."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3171\/jns.2004.101.2.0314","article-title":"A realistic brain tissue phantom for intraparenchymal infusion studies","volume":"101","author":"Chen","year":"2004","journal-title":"J. Neurosurg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.expneurol.2015.03.020","article-title":"Astrocyte roles in traumatic brain injury","volume":"275","author":"Burda","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.neuron.2012.11.021","article-title":"The Neuropathology and Neurobiology of Traumatic Brain Injury","volume":"76","author":"Blennow","year":"2012","journal-title":"Neuron"},{"key":"ref_52","first-page":"9","article-title":"The neurobiology of brain injury","volume":"2012","author":"Pekna","year":"2012","journal-title":"Cerebrum"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Laskowitz, D.T., and Grant, G. (2016). Genetic Influences in Traumatic Brain Injury. Translational Research in Traumatic Brain Injury, CRC Press\/Taylor and Francis Group.","DOI":"10.1201\/b18959"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.3171\/2009.10.FOCUS09215","article-title":"Genetic association studies in patients with traumatic brain injury","volume":"28","author":"Dardiotis","year":"2010","journal-title":"Neurosurg. Focus"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein e and Alzheimer disease: Risk, mechanisms and therapy","volume":"9","author":"Liu","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_56","first-page":"8","article-title":"Insights into the metabolic response to traumatic brain injury as revealed by 13C NMR spectroscopy","volume":"5","author":"Harris","year":"2013","journal-title":"Front. Neuroenergetics"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1517\/14728210902769601","article-title":"Emerging treatments for traumatic brain injury","volume":"14","author":"Xiong","year":"2009","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1093\/brain\/awl165","article-title":"Essential protective roles of reactive astrocytes in traumatic brain injury","volume":"129","author":"Myer","year":"2006","journal-title":"Brain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.3892\/etm.2017.4760","article-title":"GFAP expression in injured astrocytes in rats","volume":"14","author":"Zhang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6681","DOI":"10.1007\/s12035-016-0162-2","article-title":"Neuroprotection Induced by Transplanted CDK5 Knockdown Astrocytes in Global Cerebral Ischemic Rats","volume":"54","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/jnc.13213","article-title":"Heterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency","volume":"135","author":"Lebkuechner","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.neuron.2017.03.042","article-title":"iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases","volume":"94","author":"Abud","year":"2017","journal-title":"Neuron"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.stemcr.2018.03.003","article-title":"Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia","volume":"10","author":"Brownjohn","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.stemcr.2019.04.011","article-title":"Pluripotent Stem Cell-Derived Cerebral Organoids Reveal Human Oligodendrogenesis with Dorsal and Ventral Origins","volume":"12","author":"Kim","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nmeth.4304","article-title":"Fused cerebral organoids model interactions between brain regions","volume":"14","author":"Bagley","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1038\/s41592-019-0586-5","article-title":"Engineering of human brain organoids with a functional vascular-like system","volume":"16","author":"Cakir","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Shi, Y., Sun, L., Wang, M., Liu, J., Zhong, S., Li, R., Li, P., Guo, L., Fang, A., and Chen, R. (2020). Vascularized human cortical organoids (vOrganoids) model cortical development in vivo. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000705"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/10\/2683\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:10:16Z","timestamp":1760166616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/10\/2683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,7]]},"references-count":67,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["cells10102683"],"URL":"https:\/\/doi.org\/10.3390\/cells10102683","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,7]]}}}