دورية أكاديمية
أعرض في EDS

Brain Chimeroids reveal individual susceptibility to neurotoxic triggers.

التفاصيل البيبلوغرافية
العنوان: Brain Chimeroids reveal individual susceptibility to neurotoxic triggers.
المؤلفون: Antón-Bolaños N; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Faravelli I; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Faits T; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Andreadis S; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA., Kastli R; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Trattaro S; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Adiconis X; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wei A; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Sampath Kumar A; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Di Bella DJ; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Tegtmeyer M; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nehme R; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Levin JZ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Regev A; Broad Institute of MIT and Harvard, Boston, MA, USA.; Genentech, San Francisco, CA, USA., Arlotta P; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA. paola_arlotta@harvard.edu.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. paola_arlotta@harvard.edu.
المصدر: Nature [Nature] 2024 Jul; Vol. 631 (8019), pp. 142-149. Date of Electronic Publication: 2024 Jun 26.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
أسماء مطبوعة: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
مواضيع طبية MeSH: Cerebral Cortex*/cytology , Cerebral Cortex*/drug effects , Cerebral Cortex*/metabolism , Chimera*/genetics , Neurotoxins*/toxicity , Organoids*/cytology , Organoids*/drug effects , Organoids*/metabolism , Genetic Predisposition to Disease*/genetics, Female ; Humans ; Male ; Cell Lineage/drug effects ; Ethanol/adverse effects ; Ethanol/toxicity ; Genetic Variation ; Neural Stem Cells/cytology ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Phenotype ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/drug effects ; Pluripotent Stem Cells/metabolism ; Tissue Donors ; Valproic Acid/adverse effects ; Valproic Acid/toxicity
مستخلص: Interindividual genetic variation affects the susceptibility to and progression of many diseases 1,2 . However, efforts to study how individual human brains differ in normal development and disease phenotypes are limited by the paucity of faithful cellular human models, and the difficulty of scaling current systems to represent multiple people. Here we present human brain Chimeroids, a highly reproducible, multidonor human brain cortical organoid model generated by the co-development of cells from a panel of individual donors in a single organoid. By reaggregating cells from multiple single-donor organoids at the neural stem cell or neural progenitor cell stage, we generate Chimeroids in which each donor produces all cell lineages of the cerebral cortex, even when using pluripotent stem cell lines with notable growth biases. We used Chimeroids to investigate interindividual variation in the susceptibility to neurotoxic triggers that exhibit high clinical phenotypic variability: ethanol and the antiepileptic drug valproic acid. Individual donors varied in both the penetrance of the effect on target cell types, and the molecular phenotype within each affected cell type. Our results suggest that human genetic background may be an important mediator of neurotoxin susceptibility and introduce Chimeroids as a scalable system for high-throughput investigation of interindividual variation in processes of brain development and disease.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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معلومات مُعتمدة: P50 MH094271 United States MH NIMH NIH HHS; R01 MH112940 United States MH NIMH NIH HHS; RF1 MH123977 United States MH NIMH NIH HHS; U01 MH115727 United States MH NIMH NIH HHS
المشرفين على المادة: 3K9958V90M (Ethanol)
0 (Neurotoxins)
614OI1Z5WI (Valproic Acid)
تواريخ الأحداث: Date Created: 20240626 Date Completed: 20240703 Latest Revision: 20240822
رمز التحديث: 20240822
مُعرف محوري في PubMed: PMC11338177
DOI: 10.1038/s41586-024-07578-8
PMID: 38926573
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4687
DOI:10.1038/s41586-024-07578-8