基础科学和病原发生学
Jolene Wei Ling Lee1, Adeline Su Lyn Ng2, Eng-King Tan1,2
1Duke-NUS Medical School, Singapore, Singapore.
Alzheimer's & dementia : the journal of the Alzheimer's Association
|December 24, 2025
概括
这项研究使用患者衍生细胞模型CADASIL,揭示NOTCH3突变损害了血脑屏障的功能. 了解这些血管效应是CADASIL病理生理学的关键.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 干细胞生物学 干细胞生物学
背景情况:
- 大脑自体主导动脉病变与皮下心脏病发作和白脑病变 (CADASIL) 是一种与NOTCH3基因突变相关的遗传性痴呆症.
- NOTCH3突变 (MT) 变种在亚洲普遍存在,但其致病性需要功能验证.
- 血脑屏障 (BBB) 功能障碍与CADASIL的突触功能障碍有关.
研究的目的:
- 使用患者衍生的诱导多能干细胞 (iPSCs) 建模NOTCH3MT的发病因子.
- 为了研究NOTCH3 MT对BBB细胞类型内血管功能的影响.
- 为研究CADASIL建立一个3D体外BBB模型.
主要方法:
- 将患者的PBMC重新编程为iPSC,并通过CRISPR-Cas9对同位素对照进行MT校正.
- 将iPSCs分化为内皮细胞 (EC),皮细胞 (PC) 和星球细胞 (AC).
- 进行功能性测试 (血管生成,迁移,TEER) 并创建3D BBB类微组织.
主要成果:
- 在MT细胞类型 (EC,AC,PC) 中,NOTCH3的表达有所不同.
- MT ECs和PCs显示出相反的奥克卢丁趋势,表明了补偿机制.
- MT ECs表现出降低了血管生成,迁移和屏障紧张; 3D微组织形成了可 perfusable 血管.
结论:
- NOTCH3 MT对多种细胞类型具有多方面的影响,需要异质模型.
- 在CADASIL中研究血管放松调节对于了解疾病机制至关重要.
- 开发的3D BBB模型显示了在CADASIL中研究血管功能的前景.
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