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Fibrinogen triggers intial perivascular fibroblast activation in a mouse model of cortical ischemic stroke

ABSTRACT: Perivacular fibroblasts (PVFs) in the perivascular space delaminate from blood vessels, expand, express and deposit an excess of collagen I (Col I) and become an integral component of the fibrotic scar after central nervous system (CNS) disease. Here, we show that blood-derived fibrinogen deposition in the perivascular space initially induces PVF activation after photothrombosis, a mouse model of ischemic stroke. Pharmacological fibrinogen depletion reduces PVF activation and their delamination from blood vessels to build up the fibrotic scar. Fibrinogen induces beta1 integrin signaling in PVF to induce Col I expression and secretion. Single-cell RNA sequencing (scRNA-Seq) and genetic approches revealed a contribution of fibrinogen-induced perivascular macrophages to PVF activation. Finally, fibrinogen depletion abrogates PVF-astrocyte signaling and astrocyte lesion border formation, promoting neuronal survival and plasticity. Therefore, we propose that fibrinogen is a critical trigger for PVF activation and fibrotic scar formation, inhibiting neuronal regeneration after stroke.

ORGANISM(S): Mus musculus

PROVIDER: GSE291902 | GEO | 2025/12/04

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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Fibrinogen triggers intial perivascular fibroblast activation in a mouse model of cortical ischemic stroke

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