Activation of endothelial Wnt/β-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke

Shanshan Song, Huachen Huang, Xiudong Guan, Victoria Fiesler, Mohammad Iqbal H. Bhuiyan, Ruijia Liu, Shayan Jalali, Md Nabiul Hasan, Albert K. Tai, Ansuman Chattopadhyay, Srilakshmi Chaparala, Ming Sun, Donna B. Stolz, Pingnian He, Dritan Agalliu, Dandan Sun, Gulnaz Begum

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number101963
JournalProgress in Neurobiology
DOIs
StateAccepted/In press - 2020

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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