The role of a mammalian network in regulating ischemic stroke outcome II
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213177 | GEO | 2023/01/31
REPOSITORIES: GEO
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Project description:Ischemic stroke is a common acute CNS disorder leading to nearly half a million deaths per year in Europe. The high mortality is primarily owed to the limited treatment options of restoring blood flow in a narrow time window of several hours. Furthermore, inflammatory processes in the days and weeks after ischemic stroke contribute to tissue loss and neurological deficits. The key cells that influence and control this inflammatory cascade are microglia, the innate immune cells of the CNS. Microglia can be influenced and activated by e.g. lipopolysaccharide (LPS),a bacterial cell membrane component. It has been previously shown, that repetitive LPS stimuli prior to infarction (termed immunological preconditioning) lead to reduced infarct volumina in mouse models of ischemic stroke. Furthermore, our laboratory has shown, that phosphoinositide-3 kinase gamma mediates microglial functions after LPS-preconditioning. Hence, the aim of this work was to characterize proteomic alterations in microglia with (I) ischemic stroke in general in the tMCAO (transient middle cerebral artery occlusion) mouse model of ischemic stroke, (II) the influence of LPS-preconditioning on microglial proteomic alterations after tMCAO and (III) the role of PI3Ky in the microglial proteomic changes after tMCAO and preconditioning. This was done by a single LPS injection 3 days before tMCAO in wildtype mice and mice with PI3Ky knockout or knockin of the kinase dead form of PI3Ky.
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Project description:Roles of reactive perivascular astrocytes in dysregulation of the blood-brain barrier (BBB) function and cerebral perfusion are not well defined. Here, we investigated transformation of reactive astrocyte function for vascular repair after ischemic stroke by targeted deletion of astrocytic Na+/H+ exchanger isoform 1 in Gfap-CreERT2+/-;Nhe1f/f (Nhe1 Astro-KO) mice. Control Gfap-CreERT2+/-;Nhe1f/f (wild-type) mice displayed BBB damage (elevated endothelial transcytosis and intracellular vesicles) and persistent cerebral hypoperfusion in an ischemic stroke model (transient middle cerebral artery occlusion). In contrast, Nhe1 Astro-KO mice exhibited significantly less endothelial transcytosis and vesicle formation, and increased angiogenesis and cerebral blood perfusion (CBF) post-stroke. Bulk RNA-sequencing transcriptome analysis of isolated GFAP+ reactive astrocytes from wild-type and Nhe1 Astro-KO ischemic brains revealed that ~177 genes were differentially upregulated, with the Wnt7a mRNA among the top upregulated genes, along with additional Wnt pathway genes (Wnt7b, Fzd9, Fzd10, and Ndp). Abundant Wnt7a/b and β-catenin protein expression was detected in cerebral vessels of Nhe1 Astro-KO ischemic brains but not in the wild-type brains. Selective activation of Wnt/β-catenin pathway in cerebral vessels of Nhe1 Astro-KO ischemic brains was further validated using the Wnt reporter line TCF/LEF::H2B-eGFP; Gfap-CreERT2+/-;Nhe1f/f mice. Lastly, the role of Wnt/β-catenin pathway in resistance of Nhe1 Astro-KO mice to stroke-mediated BBB damage was tested by administration of Wnt/β-catenin inhibitor XAV-939. Taken together, we report that transforming reactive astrocyte function by upregulating astrocytic Wnt/β-catenin signaling activity is a novel mechanism to reduce the BBB endothelial damage, stimulate vascular repair, and restore cerebral blood flow after ischemic stroke.
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Project description:This project investigated responses of microglia in the mouse brain after an ischemic stroke. Mice were subjected to transient focal cerebral ischemia induced by 1 hour of left middle cerebral artery (MCA) occlusion followed by reperfusion. Control mice were subjected to sham surgery without the occlusion of the MCA. Three days after MCA occlusion or sham surgery, microglia were enriched from the brain by fluorescence-activated cell sorting and subjected to bulk RNA-seq. This project was closely related to our previously published dataset GSE141972; therefore, the animals had the same genetic background for comparison purposes. The animals used in this study were hemizygouse for CX3CR1(CreER), so that they can serve as wild-type controls for any conditional knockout driven by the CX3CR1(CreER) promoter.
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Project description:We aimed to investigate the influence of ischemic stroke in mice on their ribosomal mRNA in astrocytes. Therefore, we make use of the conditional Cre/LoxP System in the RiboTag mouse line in order to isolate the ribosomal mRNA of astrocytes. CreERT2 expression under the astrocyte-specific Cx43 promoter is induced by Tamoxifen injection and activates the expression of a haemagglutinin tag on ribosomal proteins. 3 weeks after Tamoxifen induction, mice were subjected to a 60 min middle cerebral artery occlusion (tMCAO), which is an established ischemic stroke model. Control mice were not further treated.
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