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Brain Chimeroids reveal individual susceptibility to neurotoxic triggers.
Antón-Bolaños, Noelia; Faravelli, Irene; Faits, Tyler; Andreadis, Sophia; Kastli, Rahel; Trattaro, Sebastiano; Adiconis, Xian; Wei, Anqi; Sampath Kumar, Abhishek; Di Bella, Daniela J; Tegtmeyer, Matthew; Nehme, Ralda; Levin, Joshua Z; Regev, Aviv; Arlotta, Paola.
Afiliación
  • Antón-Bolaños N; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • Faravelli I; 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.
  • Andreadis S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kastli R; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • Trattaro S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Adiconis X; 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.
  • Sampath Kumar A; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • Di Bella DJ; 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.
  • Nehme R; 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.
  • Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Arlotta P; Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA.
Nature ; 631(8019): 142-149, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38926573
ABSTRACT
Interindividual genetic variation affects the susceptibility to and progression of many diseases1,2. 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Organoides / Corteza Cerebral / Quimera / Predisposición Genética a la Enfermedad / Neurotoxinas Límite: Female / Humans / Male Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Organoides / Corteza Cerebral / Quimera / Predisposición Genética a la Enfermedad / Neurotoxinas Límite: Female / Humans / Male Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido