{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:30:18Z","timestamp":1787027418401,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T00:00:00Z","timestamp":1786752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301946"],"award-info":[{"award-number":["82301946"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82301946"],"award-info":[{"award-number":["82301946"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Human cerebral organoids have emerged as a promising new therapeutic strategy for cell transplantation after brain injury. Researchers have explored the short-term survival and maturation of human cerebral organoids derived from human embryonic stem cells (hESCs) in animal models. However, the long-term survival and maturation of cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) have not been studied in depth. In this study, we generated cerebral organoids from hiPSCs in a feeder-free culture system. Then, the cerebral organoids were digested into small clusters and transplanted into the frontal cerebral cortex of postnatal day 0 (P0) SCID mice. The long-term survival and maturation of the grafted cerebral organoids were evaluated at 12 months post-transplantation. Our results indicate that grafted cerebral organoids survive well and maintain their forebrain identity in vivo over a long period. The transplanted cerebral organoids showed reduced proliferative capacity, indicating a low risk of tumor formation. The majority of transplanted cells differentiated into cortical neuronal subtypes in different cortical layers in anatomical lamination at 12 months post-transplantation. In addition, a small population of grafted cerebral organoids matured into GABAergic neurons and gliocytes, including astrocytes, microglia and oligodendrocytes. Furthermore, the grafts formed synapses with the host cells and achieved vascularization in the host brain. Our study demonstrates the long-term survival and maturation of cerebral organoids derived from hiPSCs in vivo and provides evidence for the feasibility of cerebral organoids derived from hiPSCs as a potential cell transplantation therapy.<\/jats:p>","DOI":"10.3390\/cells15161466","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T08:05:41Z","timestamp":1786953941000},"page":"1466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Long-Term Survival and Maturation of Transplanted Cerebral Organoids Derived from Human Induced Pluripotent Stem Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1922-9043","authenticated-orcid":false,"given":"Xiaoli","family":"Ji","sequence":"first","affiliation":[{"name":"Departments of Pneumonology, Children\u2019s Hospital of Fudan University, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongmeng","family":"Xiong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxing","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Pneumonology, Children\u2019s Hospital of Fudan University, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,15]]},"reference":[{"key":"ref_1","first-page":"93","article-title":"Neuropathology of ischemic brain injury","volume":"92","author":"Ogata","year":"2009","journal-title":"Handb. Clin. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1001\/jamapediatrics.2014.3269","article-title":"Hypoxic-ischemic encephalopathy: A review for the clinician","volume":"169","author":"Weiss","year":"2015","journal-title":"JAMA Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.neuropharm.2008.01.005","article-title":"Mechanisms of ischemic brain damage","volume":"55","author":"Doyle","year":"2008","journal-title":"Neuropharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"435","DOI":"10.21037\/tp-20-262","article-title":"Narrative review of stem cell therapy for ischemic brain injury","volume":"10","author":"Ji","year":"2021","journal-title":"Transl. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1161\/STROKEAHA.109.573691","article-title":"Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury","volume":"41","author":"Daadi","year":"2010","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.stem.2012.01.021","article-title":"Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice","volume":"10","author":"Ma","year":"2012","journal-title":"Cell Stem. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1038\/nprot.2013.106","article-title":"Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells","volume":"8","author":"Liu","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"McIntyre, W.B., Karimzadeh, M., Riazalhosseini, Y., Khazaei, M., and Fehlings, M.G. (2022). Cell-Cell Contact Mediates Gene Expression and Fate Choice of Human Neural Stem\/Progenitor Cells. Cells, 11.","DOI":"10.3390\/cells11111741"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/7651_2017_95","article-title":"Clinically Amendable, Defined, and Rapid Induction of Human Brain Organoids from Induced Pluripotent Stem Cells","volume":"1576","author":"Crook","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Silva-Pedrosa, R., Salgado, A.J., and Ferreira, P.E. (2023). Revolutionizing Disease Modeling: The Emergence of Organoids in Cellular Systems. Cells, 12.","DOI":"10.3390\/cells12060930"},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.stemcr.2020.06.016","article-title":"Axonal Extensions along Corticospinal Tracts from Transplanted Human Cerebral Organoids","volume":"15","author":"Kitahara","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1007\/s12975-019-00773-0","article-title":"Cerebral Organoids Repair Ischemic Stroke Brain Injury","volume":"11","author":"Wang","year":"2020","journal-title":"Transl. Stroke Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1111\/cns.13286","article-title":"Cerebral organoids transplantation improves neurological motor function in rat brain injury","volume":"26","author":"Wang","year":"2020","journal-title":"CNS Neurosci. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1038\/s41380-020-00910-4","article-title":"Human cerebral organoids establish subcortical projections in the mouse brain after transplantation","volume":"26","author":"Dong","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41583-023-00760-3","article-title":"Human neuronal maturation comes of age: Cellular mechanisms and species differences","volume":"25","author":"Wallace","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1126\/science.1151526","article-title":"Induced pluripotent stem cell lines derived from human somatic cells","volume":"318","author":"Yu","year":"2007","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"ENEURO-0219","DOI":"10.1523\/ENEURO.0219-18.2018","article-title":"Vascularization and Engraftment of Transplanted Human Cerebral Organoids in Mouse Cortex","volume":"5","author":"Daviaud","year":"2018","journal-title":"eNeuro"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.stemcr.2015.01.006","article-title":"Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: Oncogenic transformation with epithelial-mesenchymal transition","volume":"4","author":"Nori","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101511","DOI":"10.1016\/j.scr.2019.101511","article-title":"Generation of two induced pluripotent stem cell (iPSC) lines from human breast milk using episomal reprogramming system","volume":"39","author":"Tang","year":"2019","journal-title":"Stem Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nprot.2017.152","article-title":"Generation of human brain region-specific organoids using a miniaturized spinning bioreactor","volume":"13","author":"Qian","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ijdevneu.2013.02.006","article-title":"Epigenetic regulation of neural stem cell fate during corticogenesis","volume":"31","author":"MuhChyi","year":"2013","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13129","DOI":"10.1073\/pnas.1002285107","article-title":"Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex","volume":"107","author":"Bedogni","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.conb.2008.05.006","article-title":"The determination of projection neuron identity in the developing cerebral cortex","volume":"18","author":"Leone","year":"2008","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1006\/exnr.1996.0013","article-title":"Use of fetal cortical grafts in hypoxic-ischemic brain injury in neonatal rats","volume":"137","author":"Elsayed","year":"1996","journal-title":"Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1016\/j.neuron.2019.10.002","article-title":"Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits","volume":"104","author":"Linaro","year":"2019","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41586-022-05277-w","article-title":"Maturation and circuit integration of transplanted human cortical organoids","volume":"610","author":"Revah","year":"2022","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nature20113","article-title":"Transplanted embryonic neurons integrate into adult neocortical circuits","volume":"539","author":"Falkner","year":"2016","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.neuron.2015.02.001","article-title":"Area-specific reestablishment of damaged circuits in the adult cerebral cortex by cortical neurons derived from mouse embryonic stem cells","volume":"85","author":"Michelsen","year":"2015","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrn2188","article-title":"Development of GABA innervation in the cerebral and cerebellar cortices","volume":"8","author":"Huang","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.neuron.2016.06.033","article-title":"GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits","volume":"91","author":"Tremblay","year":"2016","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1111\/cns.13123","article-title":"Astrocyte morphology: Diversity, plasticity, and role in neurological diseases","volume":"25","author":"Zhou","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.semcdb.2021.03.017","article-title":"Oligodendrogenesis and myelination regulate cortical development, plasticity and circuit function","volume":"118","author":"Fletcher","year":"2021","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.cell.2014.10.011","article-title":"Dynamics of oligodendrocyte generation and myelination in the human brain","volume":"159","author":"Yeung","year":"2014","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev-physiol-022516-034406","article-title":"Microglia in Physiology and Disease","volume":"79","author":"Wolf","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1093\/brain\/awac358","article-title":"Functional reconstruction of the basal ganglia neural circuit by human striatal neurons in hypoxic-ischaemic injured brain","volume":"146","author":"Ji","year":"2023","journal-title":"Brain"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1466\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:18:47Z","timestamp":1787026727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,15]]},"references-count":38,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15161466"],"URL":"https:\/\/doi.org\/10.3390\/cells15161466","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,15]]}}}