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The transcriptional landscape of pericytes in acute ischemic stroke

ABSTRACT: The current treatment options for ischemic stroke aim to achieve reperfusion but are time critical. Novel therapeutic approaches that can be given beyond the limited time window of 3 - 4.5 hours are still an unmet need to be addressed to improve stroke outcome. The lack of oxygen and glucose in the area of ischemic injury initiates a pathological cascade leading to blood-brain barrier (BBB) breakdown, inflammation and neuronal cell death, a process that may be intercepted to limit stroke progression. Pericytes located at the blood/brain interface are one of the first responders to hypoxia in stroke and therefore a potential target cell for early stroke interventions. Using single-cell RNA sequencing in a mouse model of permanent middle cerebral artery occlusion, we investigated the temporal differences in transcriptomic signatures in pericytes at 1, 12, and 24 hours after stroke compared to the contralateral hemisphere. Our results reveal a stroke-specific subcluster of pericytes that is present at 12 and 24 hours and characterized by the upregulation of genes mainly related to cytokine signalling and immune response. This study identifies temporal transcriptional changes in the acute phase of ischemic stroke that reflect the early response of pericytes to the ischemic insult and its secondary consequences and may constitute potential future therapeutic targets.

ORGANISM(S): Mus musculus

PROVIDER: GSE234052 | GEO | 2023/06/29

REPOSITORIES: GEO

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Project description:Astrogliosis is a hallmark of the response to brain ischemia, comprised of changes in gene expression and morphology. Hsp72 protects from cerebral ischemia, and although several mechanisms of protection have been investigated, effects on astrocyte activation are unknown. To identify potential mechanisms of protection, gene expression was assessed in mice subjected to middle cerebral artery (MCAO) or sham surgery, of either wildtype (WT) or Hsp72-overexpressing (Hsp72Tg) mice. After stroke, both genotypes exhibited genes related to cell death, stress response, and immune response. Furthermore, genes indicative of astrocyte activation, including cytoskeletal proteins and cytokines, were upregulated. To measure astrocyte activation after stroke, detailed histological and morphological analyses were performed in the cortical penumbra after stroke using unbiased stereology. Consistent with other reports, we observed a marked and persistent increase in glial fibrillary acidic protein (GFAP ) as soon as 3 hours after MCAO. In contrast, vimentin immunoreactivity appeared 12-24 hours after stroke, peaked at 72 hours, and returned to baseline after 30 days. Surprisingly, no change in overall astrocyte number was observed based on glutamine synthetase (GS) immunoreactivity. To determine if Hsp72Tg mice exhibited altered astrocyte activation compared to WT controls, morphological evaluation by fractal analysis was used. Overexpression of Hsp72 reduced astrocyte cell area, arbor area, and to a lesser extent fractal dimension, 72 hours following stroke. In conclusion, in vivo overexpression of Hsp72 alters gene expression following stroke, including genes involved in astrocyte activation, and decreases astrocyte activation acutely following MCAO. Thus, modulation of astrogliosis may be a neuroprotective mechanism exerted by Hsp72 after ischemia. A total of 10 samples were analyzed, with 5 of each genotype, wildtype (WT) and Hsp72-overexpressing (Hsp72Tg) mice. Of the 5 in each group, 3 received middle cerebral artery occlusion (MCAO) and 2 received a sham surgery. The sham samples serve as the controls for the MCAO samples in each genotype. All samples were taken from the ischemic or control hemisphere 24 hours after surgery.

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The transcriptional landscape of pericytes in acute ischemic stroke

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