保护性星形胶质细胞激活内皮细胞 Wnt/β-连环蛋白信号通路修复缺血性脑卒中的血脑屏障损伤。
Activation of endothelial Wnt/β-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke.
机构信息
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; The Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
出版信息
Prog Neurobiol. 2021 Apr;199:101963. doi: 10.1016/j.pneurobio.2020.101963. Epub 2020 Nov 26.
The role of astrocytes in dysregulation of blood-brain barrier (BBB) function following ischemic stroke is not well understood. Here, we investigate the effects of restoring the repair properties of astrocytes on the BBB after ischemic stroke. Mice deficient for NHE1, a pH-sensitive Na/H exchanger 1, in astrocytes have reduced BBB permeability after ischemic stroke, increased angiogenesis and cerebral blood flow perfusion, in contrast to wild-type mice. Bulk RNA-sequencing transcriptome analysis of purified astrocytes revealed that ∼177 genes were differentially upregulated in mutant astrocytes, with Wnt7a mRNA among the top genes. Using a Wnt reporter line, we confirmed that the pathway was upregulated in cerebral vessels of mutant mice after ischemic stroke. However, administration of the Wnt/β-catenin inhibitor, XAV-939, blocked the reparative effects of Nhe1-deficient astrocytes. Thus, astrocytes lacking pH-sensitive NHE1 protein are transformed from injurious to "protective" by inducing Wnt production to promote BBB repair after ischemic stroke.
星形胶质细胞在缺血性脑卒中后血脑屏障（BBB）功能失调中的作用尚不清楚。在这里，我们研究了恢复星形胶质细胞修复特性对缺血性脑卒中后 BBB 的影响。星形胶质细胞中缺乏 pH 敏感的 Na/H 交换蛋白 1（NHE1）的小鼠在缺血性脑卒中后 BBB 通透性降低，血管生成和脑血流灌注增加，与野生型小鼠相反。对纯化的星形胶质细胞进行的 bulk RNA-sequencing 转录组分析显示，突变型星形胶质细胞中有约 177 个基因表达上调，其中 Wnt7a mRNA 是上调最明显的基因之一。使用 Wnt 报告基因系，我们证实该通路在缺血性脑卒中后突变型小鼠的脑血管中上调。然而，Wnt/β-catenin 抑制剂 XAV-939 的给药阻断了 Nhe1 缺陷型星形胶质细胞的修复作用。因此，缺乏 pH 敏感的 NHE1 蛋白的星形胶质细胞通过诱导 Wnt 产生而从有害转化为“保护性”，从而促进缺血性脑卒中后的 BBB 修复。
Zotero 插件