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可扩展的下丘脑弧形神经元与人类多能干细胞的差异化适用于建模代谢和生殖障碍

Vukasin M Jovanovic^1,2, Narisu Narisu^3,2, Lori L Bonnycastle^3,2

¹National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA.

bioRxiv : the preprint server for biology

|July 15, 2024

概括

研究人员开发了一种可扩展的方法,使用人类多能干细胞 (hPSC) 来创建弧形核 (ARC) 神经元. 这些实验室培养的神经元模拟下丘脑功能,帮助研究肥胖和2型糖尿病.

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
内分泌学在内分泌学.

背景情况:

下丘脑,特别是弧形核 (ARC),对于平衡至关重要,调节能量,葡萄糖和生殖.
对这些神经元群体的翻译性研究受到人类模型的有限访问的阻碍.

研究的目的:

开发一种可扩展的,化学定义的方法,将人类多能干细胞 (hPSCs) 分化为ARC类的神经元亚群.
创建生理学相关的细胞模型,用于研究代谢和生殖障碍.

主要方法:

利用机器人细胞培养平台将hPSC分化为POMC,SST,TH和GnRH的神经元亚群.
进行了转录基因分析,用于染色质可访问性的ATAC-seq,以及分子/细胞/功能实验.
通过与人类胎儿下丘脑进行比较并测试对荷尔蒙刺激的反应来验证模型.

主要成果:

成功生成了ARC类神经元,具有来自多个hPSC线的独特特征.
证明了关键的下丘脑标记的逐步诱导和肥胖/T2D相关基因的丰富表达.
确认神经元对胰岛素,kisspeptin和Exendin-4的反应,以及适应葡萄糖/胰岛素变化的能力.

结论:

建立了一个新的,可扩展的,化学定义的平台,用于生成人类ARC神经元.
来自hPSC的ARC神经元是建模代谢和生殖疾病的宝贵资源.
这种模型为推进下丘脑功能和相关疾病研究提供了一个有前途的途径.

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