{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:03:35Z","timestamp":1790683415294,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFA1104700"],"award-info":[{"award-number":["2022YFA1104700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFA1108000"],"award-info":[{"award-number":["2024YFA1108000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Brain organoids offer an invaluable model system for studying human brain development and disease. However, the establishment of high\u2010fidelity brain organoids with multiple cell lineages, including vasculature and immune cells, remains a huge challenge. Here, we present a new strategy to generate human cerebral organoids with vasculature and microglia\u2010like cells using genetic code expansion technology via site\u2010specific protein engineering. The strategy integrates orthogonal genetic translation machinery in hPSCs, enabling temporal control of ETV2 expression and endothelial differentiation in hPSC\u2010derived cerebral organoids. The vascularized human cerebral organoids (vhCOs) exhibit coordinated development of multiple cell lineages and blood\u2010brain barrier features, and form a perfusable vascular network after being transplanted into immune\u2010deficient mice. Single\u2010nucleus RNA sequencing reveals enhanced neurovascular interactions, multi\u2010brain\u2010regional identities, diverse neuronal subtypes, and specialized endothelial subclusters in vhCOs, closely resembling the human fetal brain. Strikingly, we identify enriched microglia\u2010like cells comprising three distinct subtypes in vhCOs, which contribute to microglia\u2010vascular interactions and synergistically modulate vascular development. Upon Zika virus infection, vhCOs show neurovascular dysfunction and impaired microglia development, offering new insights into viral\u2010induced neurodevelopmental disorders. This study offers a unique platform for producing more valuable brain organoids with vasculature and immune components, opening a new avenue to advance organoid research and applications.<\/jats:p>","DOI":"10.1002\/advs.77668","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:31:12Z","timestamp":1790681472000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding Genetic Code to Generate Human Brain Organoids with Both Vasculature and Microglia\u2010Like Cells"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2601-3278","authenticated-orcid":false,"given":"Haishuang","family":"Lin","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4380-3439","authenticated-orcid":false,"given":"Yaqing","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6710-6737","authenticated-orcid":false,"given":"Hu","family":"Du","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Qin","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3359-2471","authenticated-orcid":false,"given":"Lin","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Life Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5735-6436","authenticated-orcid":false,"given":"Jianhua","family":"Qin","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"},{"name":"Division of Biotechnology Dalian Institute of Chemical Physics Chinese Academy of Sciences  Dalian China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12517"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006564\u2010w"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08172-8"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.75123"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010024\u201002157\u20108"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.09.018"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13165"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.09.043"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201028043\u2010y"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.11.030"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000705"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3791\/67491"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76707"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100586\u20105"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010biochem\u2010060713\u2010035737"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.7b00974"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-018-0052-5"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202100399"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309833"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba7606"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010020\u20100742\u20106"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.158"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.35300"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010023\u201003267\u2010x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010022\u201000901\u20103"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2015.0331"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvx133"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111538"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06002-x"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13989"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf1226"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201008351\u20107"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2023.04.016"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.04.032"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf6116"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.04.014"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.047"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201052204\u20107"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.03.042"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201006684\u20102"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.08.015"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja900553w"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-023-00684-y"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77668","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.77668","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77668","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:31:13Z","timestamp":1790681473000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.77668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":43,"alternative-id":["10.1002\/advs.77668"],"URL":"https:\/\/doi.org\/10.1002\/advs.77668","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"2026-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e77668"}}