美国洛克菲勒大学Ali H. Brivanlou研究小组取得一项新进展。他们研发出一个被称为neuruloid的自组织发育模型，其能够用于亨廷顿疾病的研究。相关论文2019年9月9日在线发表在《自然—生物技术》上。

研究人员使用微模式技术，概括了人类早期神经胚形成过程中大量几乎相同的被称为neuruloid的结构。SMAD信号通路的双重抑制以及随后骨形态发生蛋白4（BMP4）刺激诱导包含神经祖细胞、神经嵴、感觉板和表皮的neuruloid自组织。单细胞转录组学揭示了命运分化的精确身份和时间。对neuruloid自组织分子机制的研究揭示了诱导表皮边缘的pSMAD1脉冲，其与中枢神经命运的并置指定由成纤维细胞生长因子和Wnt调节的神经嵴和基板。neuruloid提供了研究人类疾病发展方面的独特机会。使用同基因亨廷顿病人类胚胎干细胞和深度神经网络分析，作为亨廷顿蛋白突变的结果，研究人员展示了特定的表型特征是如何在这个人类早期发育模型中出现的，这也提供了一种表型药物筛选的方法。

据介绍，利用标准化模型使用人类胚胎干细胞模拟正常和异常发育的潜力，是一项紧迫的挑战。

附：英文原文

Title: Self-organizing neuruloids model developmental aspects of Huntington’s disease in the ectodermal compartment

Author: Tomomi Haremaki, Jakob J. Metzger, Tiago Rito, M. Zeeshan Ozair, Fred Etoc, Ali H. Brivanlou

Issue&Volume: 2019-09-09

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 Huntingtons 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. Micropatterning generates the four ectodermal cell types of human neurulation.

DOI: 10.1038/s41587-019-0237-5

Source:https://www.nature.com/articles/s41587-019-0237-5