Regionally mapped astrocytic responses to cortical and white matter stroke show differential roles in astrocyte-induced vascular remodeling.

Abstract

Stroke is a major cause of disability. Astrocytes respond to stroke in a gradated manner, but details of that response and its consequences for tissue repair are poorly understood, particularly across brain regions and stroke subtypes. We identified phenotypically and morphologically distinct zones of reactive astrocytes in mouse models of cortical and white matter stroke. Zone-specific transcriptomic analyses revealed that cortical, but not white matter, astrocytes upregulated transcriptional programs promoting the formation of new blood vessels, a key repair mechanism. Viral gain- and loss-of-function strategies showed that astrocytic Lamc1, in particular, is an endogenous mechanism by which cortical, but not white matter, astrocytes drive remodeling of larger-caliber brain microvessels. Exogenous induction of Lamc1 in white matter astrocytes improved vessel remodeling and repair and triggered differential T cell infiltration post stroke. Astrocyte subpopulations show region-specific responses to ischemia that can be leveraged to promote repair, including astrocyte-induced vascular remodeling.