Self-organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment
Self-organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment
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DOI：
10.1038/s41587-019-0237-5
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发表时间：
2019-10-01
影响因子：
46.9
通讯作者：
Brivanlou, Ali H.
中科院分区：
文献类型：
--
作者：
Haremaki, Tomomi;Metzger, Jakob J.;Brivanlou, Ali H.
利用人类胚胎干细胞的潜力通过标准化模型模拟正常和异常发育是一项紧迫的挑战。在这里，我们使用微图案技术以大量几乎相同的结构（称为神经样体）来重现早期人类的神经系统。双SMAD抑制后刺激骨形态发生蛋白4可诱导含有神经祖细胞、神经嵴、感觉基板和表皮的神经样细胞的自组织。单细胞转录组学揭示了命运规范的精确身份和时间。对神经样自组织分子机制的研究揭示了边缘处的 pSMAD1 脉冲诱导表皮，其与中枢神经命运的并置指定了由成纤维细胞生长因子和 Wnt 调节的神经嵴和基板。神经样细胞为研究人类疾病的发育方面提供了独特的机会。利用同基因亨廷顿病人类胚胎干细胞和深度神经网络分析，我们展示了由于突变亨廷顿蛋白而在我们的早期人类发育模型中如何出现特定的表型特征，概述了表型药物筛选的方法。
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.