利用源自人诱导多能干细胞的脑微血管内皮细胞建立脑缺血的体外模型。

In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells.

作者信息

Kokubu Yasuhiro, Yamaguchi Tomoko, Kawabata Kenji

机构信息

Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.

Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.

出版信息

Biochem Biophys Res Commun. 2017 Apr 29;486(2):577-583. doi: 10.1016/j.bbrc.2017.03.092. Epub 2017 Mar 21.

Abstract

Brain-derived microvascular endothelial cells (BMECs), which play a central role in blood brain barrier (BBB), can be used for the evaluation of drug transport into the brain. Although human BMEC cell lines have already been reported, they lack original properties such as barrier integrity. Pluripotent stem cells (PSCs) can be used for various applications such as regenerative therapy, drug screening, and pathological study. In the recent study, an induction method of BMECs from PSCs has been established, making it possible to more precisely study the in vitro human BBB function. Here, using induced pluripotent stem (iPS) cell-derived BMECs, we examined the effects of oxygen-glucose deprivation (OGD) and OGD/reoxygenation (OGD/R) on BBB permeability. OGD disrupted the barrier function, and the dysfunction was rapidly restored by re-supply of the oxygen and glucose. Interestingly, TNF-α, which is known to be secreted from astrocytes and microglia in the cerebral ischemia, prevented the restoration of OGD-induced barrier dysfunction in an apoptosis-independent manner. Thus, we could establish the in vitro BBB disease model that mimics the cerebral ischemia by using iPS cell-derived BMECs.

摘要

脑源性微血管内皮细胞(BMECs)在血脑屏障(BBB)中起核心作用,可用于评估药物向脑内的转运。尽管已经报道了人BMEC细胞系,但它们缺乏屏障完整性等原始特性。多能干细胞(PSCs)可用于多种应用,如再生治疗、药物筛选和病理学研究。在最近的研究中,已建立了从PSCs诱导生成BMECs的方法,从而能够更精确地研究体外人血脑屏障功能。在此,我们使用诱导多能干细胞(iPS)来源的BMECs,研究了氧葡萄糖剥夺(OGD)和OGD/复氧(OGD/R)对血脑屏障通透性的影响。OGD破坏了屏障功能,通过重新供应氧气和葡萄糖,功能障碍迅速恢复。有趣的是,已知在脑缺血中由星形胶质细胞和小胶质细胞分泌的肿瘤坏死因子-α(TNF-α)以非凋亡依赖的方式阻止了OGD诱导的屏障功能障碍的恢复。因此,我们可以利用iPS细胞来源的BMECs建立模拟脑缺血的体外血脑屏障疾病模型。

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