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Self-organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment

Item Type:Article
Title:Self-organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment
Creators Name:Haremaki, T. and Metzger, J.J. and Rito, T. and Ozair, M.Z. and Etoc, F. and Brivanlou, A.H.
Abstract:Harnessing the potential of human embryonic stem cells to mimic normal and aberrant development with standardized models is a pressing challenge. Here we use micropattern technology to recapitulate early human neurulation in large numbers of nearly identical structures called neuruloids. Dual-SMAD inhibition followed by bone morphogenic protein 4 stimulation induced self-organization of neuruloids harboring neural progenitors, neural crest, sensory placode and epidermis. Single-cell transcriptomics unveiled the precise identities and timing of fate specification. Investigation of the molecular mechanism of neuruloid self-organization revealed a pulse of pSMAD1 at the edge that induced epidermis, whose juxtaposition to central neural fates specifies neural crest and placodes, modulated by fibroblast growth factor and Wnt. Neuruloids provide a unique opportunity to study the developmental aspects of human diseases. Using isogenic Huntington's disease human embryonic stem cells and deep neural network analysis, we show how specific phenotypic signatures arise in our model of early human development as a consequence of mutant huntingtin protein, outlining an approach for phenotypic drug screening.
Keywords:Cell Culture Techniques, Cell Differentiation, Cell Line, Ectoderm, Embryonic Stem Cells, Huntington Disease, Neurogenesis, Neurulation, Telencephalon
Source:Nature Biotechnology
Publisher:Nature Publishing Group
Page Range:1198-1208
Date:October 2019
Official Publication:https://doi.org/10.1038/s41587-019-0237-5
PubMed:View item in PubMed

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