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

doi:10.1016/j.pneurobio.2020.101963

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

Prog Neurobiol. 2021 Apr:199:101963. doi: 10.1016/j.pneurobio.2020.101963. Epub 2020 Nov 26.

Authors

Shanshan Song¹, Huachen Huang², Xiudong Guan², Victoria Fiesler¹, Mohammad Iqbal H Bhuiyan¹, Ruijia Liu², Shayan Jalali², Md Nabiul Hasan¹, Albert K Tai³, Ansuman Chattopadhyay⁴, Srilakshmi Chaparala⁴, Ming Sun⁵, Donna B Stolz⁵, Pingnian He⁶, Dritan Agalliu⁷, Dandan Sun⁸, Gulnaz Begum⁹

Affiliations

¹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; The Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA.
² Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
³ Department of Immunology, Tufts University, Boston, MA, USA.
⁴ Molecular Biology-Information Service, Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA, USA.
⁷ Departments of Neurology, Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
⁸ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; The Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA; Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA, USA.
⁹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; The Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: gub6@pitt.edu.

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.

Keywords: Angiogenesis; Astrocytes; Blood-Brain barrier; Na(+)/H(+)exchanger isoform-1; Wnt/β-catenin signaling.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Astrocytes / metabolism
Blood-Brain Barrier* / metabolism
Brain Ischemia*
Ischemic Stroke*
Mice
Wnt Signaling Pathway
beta Catenin / genetics
beta Catenin / metabolism

Substances

CTNNB1 protein, mouse
beta Catenin

Abstract

Publication types

MeSH terms

Substances

Grants and funding