Expression data from reactive astrocytes acutely purified from young adult mouse brains
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Jennifer Zamanian
PROVIDER: E-GEOD-35338 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two different mouse injury models, ischemic stroke and neuroinflammation.
2012-05-02 | GSE35338 | GEO
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.
2013-01-11 | E-GEOD-28731 | biostudies-arrayexpress
Project description:Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand, lipopolysaccharide (LPS) or the TLR9 ligand, unmethylated CpG ODNs prior to transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain and blood genomic profiles in response to preconditioning with these TLR ligands and to preconditioning via exposure to brief ischemia. The experiment is a comparison of multiple treatment groups with sampling at multiple time points. The objective is to identify differentially regulated genes associated with preconditioning. Time points are examined both following preconditioning alone and following subsequent ischemic challenge (middle cerebral artery occlusion (MCAO)). Brain ipsilateral cortex tissue and blood were collected and processed from each animal. 6 experimental conditions: (n=3-4 mice/condition) LPS treated (i.p. 0.2mg/kg) + ischemic challenge (45min MCAO) CpG treated (i.p. 0.8mg/kg) + ischemic challenge (45min MCAO) Saline treated (i.p.) + ischemic challenge (45min MCAO) brief ischemia (12 min MCAO) + ischemic challenge (45min MCAO) Sham of brief ischemia (12 min) + ischemic challenge (45min MCAO) Non-treated + ischemic challenge (45min MCAO) Time points: Pre-ischemic challenge 3hr 24hr 72hr Post-ischemic challenge 3hr 24hr Unhandled (6 mice)-BASELINE
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Project description:Reactive astrocytes play critical roles after brain injury, but their precise function is not well defined, particularly in humans and nonhuman primates (NHPs). Here, we utilized single nuclei transcriptomics to characterize astrocytes after ischemic stroke in the primary visual cortex (V1) of the marmoset monkey. We observed nearly complete segregation between stroke and control astrocyte clusters. Screening the top 30 differentially expressed genes to identify candidates that might limit stroke recovery, we discovered that RTN4A/ NogoA, a neurite-outgrowth inhibitory protein previously associated specifically with oligodendrocytes but not astrocytes, was expressed in a majority of reactive astrocytes. Robust NogoA upregulation on reactive astrocytes following stroke was confirmed in both the marmoset and human brain, whereas rodents exhibited only a marginal change in NogoA expression following stroke. Further, in vivo and in vitro studies determined that NogoA mediated an anti-inflammatory response which likely contributes to limiting deeper infiltration of peripheral macrophages into the surviving parenchyma during the subacute post-stroke period. These findings are directly relevant to the development of NogoA-targeting therapies designed for clinical use shortly after ischemic stroke. In addition, our data have uncovered the complexity of astrocyte responses in primates, which highlights the importance of preclinical model selection for discovery research designed to identify novel therapeutics for brain injury.
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Project description:We employed DNA microarray to identify genes differentially regulated by salidroside in ischemic brain of MCAO rats. With a cut of p < .01 and 2-fold change, we found that 121 genes were upregulated and 142 genes were down-regulated in the MCAO group, compared to the sham group. Administration of salidroside (1 h after reperfusion, daily for 6 d) enhanced 28 transcripts and suppressed 16 transcripts. The genes involved in neuroplasticity and oxygen carrier were further confirmed by qRT-PCR. Our data suggest that salidroside could regulate neuroplasticity in post-ischemic stroke, in addition to its neuroportective function. MCAO rats were injected intraperitoneally with salidroside (50 mg/kg body weight) or vehicle (saline) once a day for 6 d, commencing 1 h after reperfusion (n=3 /group). Ischemic brain was dissected for RNA extraction. Differential gene expression regulated by salidroside were analysed by microarray and subsequently confirmed by qRT-PCR.
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Project description:The role of matrilin-3 in the brain, an extracellular matrix component in cartilage, is unknown. Here, we identify matrilin-3 decreased in reactive astrocytes but unchanged in neurons after ischemic stroke in animals. Importantly, it is declined in serum of patients with acute ischemic stroke. Genetic or pharmacological inhibition or supplementation of matrilin-3 aggravates or reduces brain injury, astrocytic cell death and glial scar, respectively, but has no direct effect on neuronal cell death. RNA-sequencing demonstrates that Matn3−/− mice display an increased inflammatory response profile in the ischemic brain, including the NF-κB signaling pathway. Both endogenous and exogenous matrilin-3 reduce inflammatory mediators. Mechanistically, extracellular matrilin-3 enters astrocytes via caveolin-1-mediated endocytosis. Cytoplasmic matrilin-3 translocates into the nucleus by binding to NF-κB p65, suppressing inflammatory cytokines transcription. Extracellular matrilin-3 binds to BMP-2, blocking BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection at least partially via suppressing astrocyte-mediated neuroinflammation.
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Project description:To comprehensively understand the mechanism by which MYPT1 modulates the phenotypic switching of VSMCs after ischemic stroke, the proteins of cortical small vessel from MYPT1SMKO and WT mice subjected to MCAO or sham group were collected for proteomic screening.
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Project description:Reactive astrocytes are detrimental or protective in ischemic stroke. However, the mechanisms of these effects are not entirely clear. We investigated the heterogeneity of mice astrocytes 12 h after cerebral ischemia-reperfusion via Single-cell RNA sequencing. We acquired astrocyte subclusters’ transcriptional characteristics involving diversified functions. We identified 9 genes as potential therapeutic targets and 6 genes were specific to astrocyte subcluster 2. Additionally, we explored the effects of melatonin and stattic on the transformation of astrocytes to the A2 phenotype. TTC stain, grip strength test and immunofluorescence were used. We revealed melatonin promoted the transformation of astrocytes to the A2 phenotype, the effect was related to STAT3 and inhibited by Stattic. Our study may lay a foundation for untangling the difference between astrocyte subclusters 12 h after stroke and elucidating the mechanisms of A2 astrocyte transformation 3 d after stroke.
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Project description:Middle cerebral artery occlusion (MCAo) in rat represent the ischemic stroke in human. Rodents subjected to MCAo and treated with venom phospholipase A2 showed reduction in infarct volume after 24hours of stroke. We studied the global gene expression of the reduction in infarct volume using Affymetrix Gene Chips. We analysed all the genes that were up or down regulated in the study. Total RNA isolated from sham, MCAo and MCAo+nPLA rat brains, was pooled to minimize inter-individual variation and hybridized to each array of the RAE-230A or U34A GeneChipTM according to protocols described in the GeneChipTM expression analysis package (Affymetrix, CA).
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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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