诺奇3指导脑壁细胞与人类多能干细胞衍生的神经区分
Benjamin D Gastfriend1, Margaret E Snyder1, Hope E Holt1
1Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
Science advances
|February 2, 2024
概括
激活神经细胞中的Notch3信号,成功地引导它们分化为大脑壁画细胞. 这种新方法改善了脑壁细胞的转录形状,以获得更好的血脑屏障模型.
科学领域:
- 神经科学是一个神经科学.
- 发展生物学 发展生物学
- 细胞生物学 细胞生物学
背景情况:
- 大脑壁画细胞对于血脑屏障 (BBB) 的发展和功能至关重要.
- 目前的体外模型显示关键壁细胞基因的表达不足,例如NOTCH3.3.
- 需要改进的模型来研究BBB调节和壁细胞生物学.
研究的目的:
- 调查激活Notch3信号是否可以将神经分化引导到脑壁细胞中.
- 在体外增强人类大脑壁画细胞的转录特征.
- 建立一个与发展相关的协议,用于产生脑壁画细胞.
主要方法:
- 在人类多能干细胞 (hPSC) 衍生的神经脊柱中,Notch3细胞内域 (N3ICD) 的过度表达.
- 对壁画细胞标记物基因表达的分析.
- 评估细胞外基质的产生和与内皮细胞的自我组装.
- KATP通道的功能性特征.
- 染色体免疫沉降测序 (ChIP-seq) 用于识别Notch3向基因.
主要成果:
- N3ICD过度表达成功诱导了关键的壁细胞标记物 (PDGFRβ,TBX2,FOXS1,KCNJ8,SLC6A12) 和内源性Notch3.3.
- 来自N3ICD的壁画细胞产生了细胞外基质并与内皮细胞自组装.
- 在分化的壁画细胞中观察到功能性的KATP通道.
- 在这种差异化背景下,ChIP-seq表示Notch3直接调节有限的基因组.
结论:
- 诺奇3信号激活足以驱动神经分化到脑壁细胞.
- 这项研究为产生脑壁细胞提供了一种新的,发育相关的协议.
- 这些发现为研究BBB和相关的血管功能提供了改进体外模型的途径.
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