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在iPSC衍生的疾病模型中扩大GABAergic神经元多样性

Ruiqi Hu^1,2,3,4,5, Linda L Boshans^1,2,3,4,5, Bohan Zhu⁶

¹Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

bioRxiv : the preprint server for biology

|December 16, 2024

概括

我们开发了一种新方法,可以有效地从人类干细胞中产生多样化的GABAergic神经元,帮助研究神经发育和精神疾病.

科学领域:

神经科学是一个神经科学.
干细胞生物学干细胞生物学
发展生物学发展生物学

背景情况:

GABAergic内部神经元对于神经电路功能至关重要,它们的功能障碍与神经发育和精神疾病有关.
目前用于将人类多能干细胞 (PSC) 分化为神经元的方法面临着不完整分化和可变性等挑战.

研究的目的:

开发一种有效的策略,从人类PSC中产生多样化,区域特定的GABAergic神经元类型.
描述这些诱导神经元 (iN) 的细胞异质性和调节机制.
为了建模特定基因突变对GABAergic神经元发育的影响.

主要方法:

转录因子ASCL1和DLX2的过度表达与双SMAD和WNT抑制相结合.
单细胞测序用于分析细胞异质性和基因表达.
该协议的应用用于研究ADNP综合征突变.

主要成果:

新的协议有效地产生多种GABAergic iNs,包括有模式的 iNs (类似于质突出和新皮质) 和PSC衍生的 iNs (类似于下丘脑和丘脑神经元).
两种IN类型都富含与神经发育和精神疾病相关的基因.
已经证明ADNP综合征突变会破坏GABAergic命运规范和突触传输.

结论:

这项研究提供了互补的GABAergic iN模型 (模式和PSC衍生) 用于研究不同的神经元亚型,大脑区域和疾病背景.
开发的协议为研究神经发育和精神疾病中的分子机制提供了一个强大的平台.
这些发现扩大了使用人类干细胞衍生神经元的疾病建模工具包.

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