Mus musculus
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ABSTRACT:
PROVIDER: PRJNA281992 | ENA |
REPOSITORIES: ENA
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Project description:Injury to the adult brain induces activation of resident astrocytes, which serves as a compensatory response modulating tissue damage and recovery. However, the mechanism governing astrocyte activation and the role of reactive astrocytes remain largely unknown. Here we show that SOX2, a transcription factor critical for stem cells and brain development, is also required for injury-induced activation of adult cortical astrocytes. Genome-wide ChIP-seq analysis reveals that SOX2 binds to regulatory regions of genes associated with signaling pathways controlling reactive gliosis, such as Socs3, Nr2e1, Notch1, and Akt2. Inducible deletion of Sox2 in adult astrocytes greatly diminishes their response to traumatic injury and, most unexpectedly, restricts injury-induced cortical loss. Together, these results uncover an essential role of SOX2 in terminally differentiated cells and implicate that SOX2-dependent reactive astrocytes may be targeted for regeneration after traumatic brain injury.
2018-02-22 | GSE85213 | GEO
Project description:The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system (CNS) degeneration and repair remain poorly understood. Here, we show injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2)1,2, which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cAMP derived from soluble adenylyl cyclase (sAC) and show proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell (RGC) survival. Finally, we report a new, therapeutically tractable viral vector to specifically target optic nerve head astrocytes and show elevating nuclear or depleting cytoplasmic cAMP in reactive astrocytes inhibits deleterious immune cell infiltration and promotes RGC survival after optic nerve injury. Thus, soluble adenylyl cyclase and compartmented, nuclear- and cytoplasmic-localized cAMP in reactive astrocytes act as a molecular switch for neuroprotective astrocyte reactivity that can be targeted to inhibit microglial activation and neurotoxic astrocyte differentiation to therapeutic effect. These data expand upon and define new reactive astrocyte subtypes and represents a novel step towards the development of gliotherapeutics for the treatment of glaucoma and other optic neuropathies.
2023-12-11 | GSE245816 | GEO
Project description:Astrocytes differentiate into a spectrum of neurotoxic and neuroprotective reactive subpopulations after CNS injury and in disease. In astrocyte conditional ADCY10 (sAC) knockout mice, reactive astrocytes exhibit a shift towards neurotoxic phenotypes implicating sAC as a critical regulator of neuroprotective astrocyte differentiation.
2023-12-11 | GSE237675 | GEO
Project description:Transcriptome profiling of mice overexpressing a constitutively active form of CREB in astrocytes (VP16-CREB) vs WT mice, both in normal conditions and after a focal cryolesion (C) in the parietal cortex. Goal is to determine which astrocytic genes are responsible for the neuroprotection we observed in VP16-CREB mice after injury.
2016-04-27 | GSE68187 | GEO
Project description:Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes. Fundamental features of these cells are poorly understood. Here, using temporal transcriptome analysis of Aldh1l1-expressing local astrocytes we showed that after CNS injury, local mature astrocytes dedifferentiated, proliferated, and become transcriptionally reprogrammed to permanently altered new functional states, with persisting downregulation of molecules associated with astrocyte-neuron interactions, and upregulation of molecules associated with wound healing, microbial defence, and interactions with stromal and immune cells. Our findings show that at CNS injury sites, local mature astrocytes proliferate and adopt canonical features of essential wound repair cells that persist in adaptive states and are the predominant source of neuroprotective borders that re-establish CNS integrity by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.
2023-08-28 | GSE241628 | GEO
Project description:Astrocytes are abundant glial cells in the central nervous system (CNS) that play important roles in cerebral ischemia-reperfusion injury. Following brain ischemia, astrocytes can trigger endogenous neuroprotective mechanisms such as neurogenesis, regulation of inflammation, transfer of mitochondria, and defense against oxidative stress. Transforming growth factor beta 1 (TGF-β1) is known as an injury-related cytokine, particularly associated with neurogenesis, neuronal migration, inflammatory reactions, and astrocyte scar formation in response to brain injury. TGF-β1 is closely related to ischemia-reperfusion brain injury and plays a significant role as both effectors and targets of I/R brain injury. Upregulation of endogenous TGF-β1 in neurons may contribute to preventing apoptosis after ischemic insult. TGF-β1 exerts dynamic effects in tissues through autocrine and paracrine signaling pathways as a secretory factor. The current study suggests that the multiple functions exerted by astrocytes might potentially be mediated by TGF-β1 signaling, raising the idea that astrocytes could be a potential therapeutic target for neuroprotection as sources or targets of TGF-β1. However, few studies are currently available on the effects of TGF-β1 on astrocytes after ischemia-reperfusion brain injury. Although current research shows that transforming growth factor-beta acts as a neuroprotective agent in cerebral ischemia, its specific mechanism is still not completely clear. In this study, RNA sequencing analysis was performed to investigate the potential mechanism of astrocytes pretreated with TGF-β1. Our study found that TGF-β1 mediates the upregulation of DUSP4 in astrocytes, which plays a neuroprotective role after ischemia-reperfusion injury. Overexpression of TGF-β1 inhibits the activation of astrocytes, accompanied by decreased levels of inflammatory factors and reactive oxygen species (ROS), while promoting the transfer of mitochondria between astrocytes and neurons. This enhanced neuron survival and axonal regeneration after injury. Hence, this study provides further insights into strategies for inhibiting neurological impairment and suggests a potential therapeutic target after ischemia-reperfusion injury.
2025-01-08 | GSE253273 | GEO
Project description:Following contusive spinal injury astrocytes undergo inflammatory activation and proliferation in a process known as astrogliosis. Reactive astrocytes are attractive therapeutic targets as they sit central to many of the immune recruitment, injury response, and tissue healing processes of the spinal cord. However, methods of targeted expression of exogenous therapeutic genes within astrocytes must be validated to not alter the normal immunological involvement of astrocytes. To investigate the effect of transgene expression within astrocytes upon the immunological state of the contused cord, we injected the astrocyte-selective AAV5-GfaABC1D-dYFP reporter vector into an animal model of moderate contusive spinal cord injury. Bulk RNA microarrays were used to assess transcriptomic changes of the perilesional tissue.
2021-08-26 | GSE182796 | GEO
Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4
2015-11-04 | E-GEOD-74614 | biostudies-arrayexpress
Project description:After central nervous system injury, a rapid neuroinflammatory response is induced. This response can be both beneficial and detrimental to neuronal survival in the first few days and increase the risk for neurodegeneration if it persists. Semaphorin4B (Sema4B), a transmembrane protein primarily expressed by cortical astrocytes, has been shown to play a role in neuronal cell death following injury. Our study shows that neuroinflammation is attenuated in Sema4B knockout mice and microglia/macrophage activation is reduced after cortical stab wound injury. In vitro, recombinant Sema4B enhances the activation of microglia following injury, suggesting astrocytic Sema4B functions as a ligand. Moreover, injury-induced activation of microglia is attenuated in the presence of Sema4B knockout astrocytes compared to heterozygous astrocytes. In vitro, experiments indicate Plexin-B2 is the Sema4B receptor on microglia. Consistent with this, microglia-specific Plexin-B2 knockout mice, similar to Sema4B knockout mice, also show a reduction in microglial activation after cortical injury. Finally, in Sema4B/Plexin-B2 double heterozygous mice, microglial activation is also reduced after injury, thus supporting the idea that both Sema4B and Plexin-B2 are part of the same signaling pathway. Taken together, we propose a model in which following injury, astrocytic Sema4B enhances the pro-inflammatory response of microglia/macrophages via Plexin-B2, leading to increased neuroinflammation.
2024-02-28 | GSE230069 | GEO
Project description:Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here, we introduce a novel glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled rapid derivation of astroglial cells, which account for 25-31% of the cell population within eight to ten weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within the organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates proinflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling plays a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.
2024-01-16 | GSE185472 | GEO