TY - JOUR
T1 - Activation of endothelial Wnt/β-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke
AU - Song, Shanshan
AU - Huang, Huachen
AU - Guan, Xiudong
AU - Fiesler, Victoria
AU - Bhuiyan, Mohammad Iqbal H.
AU - Liu, Ruijia
AU - Jalali, Shayan
AU - Hasan, Md Nabiul
AU - Tai, Albert K.
AU - Chattopadhyay, Ansuman
AU - Chaparala, Srilakshmi
AU - Sun, Ming
AU - Stolz, Donna B.
AU - He, Pingnian
AU - Agalliu, Dritan
AU - Sun, Dandan
AU - Begum, Gulnaz
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.pneurobio.2020.101963
DO - 10.1016/j.pneurobio.2020.101963
M3 - Article
C2 - 33249091
AN - SCOPUS:85097042126
SN - 0301-0082
VL - 199
JO - Progress in Neurobiology
JF - Progress in Neurobiology
M1 - 101963
ER -