{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:15:28Z","timestamp":1791512128367,"version":"4.3.4"},"reference-count":89,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"815","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,9,10]]},"abstract":"<jats:p>Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are essential for the formation of myelin sheaths and pivotal for maintaining axonal integrity and conduction. Disruption of these cells and the myelin sheaths they produce is a hallmark of demyelinating conditions like multiple sclerosis or those resulting from certain drug side effects, leading to profound neurological impairments. In this study, we created a human brain organoid comprising neurons, astrocytes, and myelinating oligodendrocytes. By integrating induced pluripotent stem cell\u2013derived microglia, we endowed these myelinated human brain organoids (MHBOs) with immune characteristics. MHBOs with microglia (MHBOs +MG) enabled the investigation of demyelination and remyelination\u2014a process in which myelin sheaths are regenerated\u2014in a human context. After toxin-induced demyelination, we observed a reduction in myelin followed by subsequent self-driven remyelination. Proteomic and transcriptomic analyses provided a molecular signature of demyelination and myelin recovery indicating a central role for microglia in the remyelination process. Furthermore, the application of the pro-remyelinating compounds clemastine, XAV939, and BQ3020 further enhanced remyelination in MHBOs +MG but was ineffective in the absence of microglia. Cross-validation of our findings in mouse cerebellar slice cultures confirmed that the pro-remyelinating compounds were effective ex vivo, suggesting the translational potential of our MHBOs +MG model.<\/jats:p>","DOI":"10.1126\/scitranslmed.adp7047","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:58:14Z","timestamp":1757527094000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":23,"title":["Human myelinated brain organoids with integrated microglia as a model for myelin repair and remyelinating therapies"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4124-9212","authenticated-orcid":true,"given":"Simona","family":"Lange","sequence":"first","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0361-4636","authenticated-orcid":true,"given":"Martin","family":"Ebeling","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ath\u00e9na","family":"Loye","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8956-0116","authenticated-orcid":true,"given":"Florian","family":"Wanke","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1759-3223","authenticated-orcid":true,"given":"Juliane","family":"Siebourg-Polster","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2830-8106","authenticated-orcid":true,"given":"Tania J. J.","family":"Sudharshan","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0345-1910","authenticated-orcid":true,"given":"Franziska","family":"V\u00f6llmy","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5216-9818","authenticated-orcid":true,"given":"Jakub","family":"Kralik","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9reng\u00e8re","family":"Vidal","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3602-4234","authenticated-orcid":true,"given":"Kerstin","family":"Hahn","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6351-8374","authenticated-orcid":true,"given":"Lynette C.","family":"Foo","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5602-0850","authenticated-orcid":true,"given":"Jan","family":"Hoeber","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2022.1041961"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2016.06.005"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.757360"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1220845"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2019.134645"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a041371"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-008-1004-6"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2480"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.10.011"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2020.09.009"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0842-3"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073461"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2237050100"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3358"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1747-1"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0184-2"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05534-y"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007814117"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101860"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05219-6"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22179473"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.04.006"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0316-9"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.14573\/altex.1609122"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-23477-2"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.617860"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci11020272"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/35000226"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.jnen.0000248559.83573.71"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.04.016"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2019.108537"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0892-0362(02)00213-1"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2855"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3618"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32346-2"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-29333-1"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01892-1"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2021.06.011"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-00757-6"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1426"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113574"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1103709"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22698"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(01)00136-4"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022623"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23583"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028993"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21266"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24148"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.10.2.535"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2004.06.015"},{"key":"e_1_3_2_53_2","first-page":"193","article-title":"Remyelination in experimental models of toxin-induced demyelination","volume":"318","author":"Blakemore W. F.","year":"2008","unstructured":"W. F. Blakemore, R. J. Franklin, Remyelination in experimental models of toxin-induced demyelination. Curr. Top. Microbiol. Immunol. 318, 193\u2013212 (2008).","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2005.03.008"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.712241"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-49868-6"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0234493"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13087"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.120.3.649"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2702"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1136\/bcr.05.2009.1908"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv289"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30347-1"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2015.08.028"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-019-0705-7"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-86191-5"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1111\/cen3.12208"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni754"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1186\/2051-5960-2-53"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-021-01306-3"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232415983"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200112)31:12<3726::AID-IMMU3726>3.0.CO;2-O"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00412"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2011.06.023"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.02.090"},{"key":"e_1_3_2_77_2","unstructured":"S. Andrews FastQC (Babraham Institute 2010); https:\/\/bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_2_79_2","unstructured":"Broad Institute Picard Toolkit (2018 GitHub); http:\/\/broadinstitute.github.io\/picard\/."},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw354"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks461"},{"key":"e_1_3_2_84_2","unstructured":"ribiosNGS: Next-generation sequencing data analysis with ribios (GitHub); https:\/\/github.com\/bedapub\/ribiosNGS."},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_3_2_86_2","volume-title":"A","author":"Bhuva D.","year":"2023","unstructured":"D. Bhuva, G. Smyth, A. Garnham, msigdb: An ExperimentHub package for the Molecular Signatures Database (MSigDB) (BioConductor, 2023); https:\/\/bioconductor.org\/packages\/msigdb."},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt111"},{"key":"e_1_3_2_88_2","doi-asserted-by":"crossref","unstructured":"T. J. Deerinck E. A. Bushong M. H. Ellisman A. Thor Preparation of biological tissues for serial block face scanning electron microscopy (SBEM) v1 protocols.io (2022); 10.17504\/protocols.io.36wgq7je5vk5\/v1.","DOI":"10.17504\/protocols.io.b5c2q2ye"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9072-6_3"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.346538"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adp7047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:58:20Z","timestamp":1757527100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adp7047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":89,"journal-issue":{"issue":"815","published-print":{"date-parts":[[2025,9,10]]}},"alternative-id":["10.1126\/scitranslmed.adp7047"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adp7047","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]},"assertion":[{"value":"2024-04-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-17","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadp7047"}}