Neuron-Derived Estrogen is Critical for Astrocyte Activation and Neuroprotection of the Ischemic Brain
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ABSTRACT:
PROVIDER: PRJNA601790 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR10905400.fastq.gz | Fastqsanger.gz | |||
| SRR10905397.fastq.gz | Fastqsanger.gz | |||
| SRR10905398.fastq.gz | Fastqsanger.gz | |||
| SRR10905399.fastq.gz | Fastqsanger.gz |
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Project description:We examined the transcriptional changes modulated in ischemic brain of fore brain specific aromatase knockout mice (FBN-ARO-KO) by performing global transcriptome analysis.Total RNA was isolated from FLOX and FBN-ARO-KO mice that underwent 20-minute CCA occlusion, followed by 24-hour reperfusion. The collected hippocampi samples were subjected to RNA isolation and Illumina TruSeq RNA sample preparation and sequencing was done using UT Health San Antonio genomics core facility protocol. We observed that some of the key pathways that regulate astrocyte reactivity, such as RhoA signaling, actin-based motility by Rho signaling, signaling by Rho family GTPases, and protein ubiquitination, NRF2-mediated oxidative stress response pathways were significantly altered in FBN-ARO-KO+GCI mice.
2020-10-13 | GSE143836 | GEO
Project description:17β-Estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but the functions of neuron-derived E2 in the ischemic brain are unclear. Here, we used a forebrain neuron-specific aromatase KO (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain and determine its roles after global cerebral ischemia. We demonstrated that ovariectomized female FBN-ARO-KO mice exhibited significantly attenuated astrocyte activation, astrocytic aromatization, and decreased hippocampal E2 levels compared with FLOX mice. Furthermore, FBN-ARO-KO mice had exacerbated neuronal damage and worse cognitive dysfunction after global cerebral ischemia. Similar results were observed in intact male mice. RNA-seq analysis revealed alterations in pathways and genes associated with astrocyte activation, neuroinflammation, and oxidative stress in FBN-ARO-KO mice. The compromised astrocyte activation in FBN-ARO-KO mice was associated with robust downregulation of the astrocyte-derived neurotrophic factors, BDNF and IGF-1, as well as the astrocytic glutamate transporter, GLT-1. Νeuronal FGF2, which acts in a paracrine manner to suppress astrocyte activation, was increased in FBN-ARO-KO neurons. Interestingly, blocking FGF2 signaling by central injection of FGFR3-neutralizing antibody was able to reverse the diminishment in neuroprotective astrocyte reactivity, and attenuate neuronal damage in FBN-ARO-KO mice. Moreover, in vivo E2 replacement suppressed FGF2 signaling and rescued the compromised reactive astrogliosis and cognitive deficits. Collectively, our data provide novel genetic evidence for a beneficial role of neuron-derived E2 in astrocyte activation, neuroprotection, and cognitive preservation following ischemic injury to the brain.SIGNIFICANCE STATEMENT Following cerebral ischemia, astrocytes become highly reactive and can exert neuroprotection through the release of neurotrophic factors and clearance of neurotoxic glutamate. The current study advances our understanding of this process by demonstrating that neuron-derived 17β-estradiol (E2) is neuroprotective and critical for induction of reactive astrocytes and their ability to produce astrocyte-derived neurotrophic factors, BDNF and IGF-1, and the glutamate transporter, GLT-1 after ischemic brain damage. These beneficial effects of neuron-derived E2 appear to be due, at least in part, to suppression of neuronal FGF2 signaling, which is a known suppressor of astrocyte activation. These findings suggest that neuron-derived E2 is neuroprotective after ischemic brain injury via a mechanism that involves suppression of neuronal FGF2 signaling, thereby facilitating astrocyte activation.
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Project description:NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. RNA-sequencing was conducted to confirm neuronal recovery after cell conversion at the mRNA level.
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Project description:Background: Neonatal Hypoxic-Ischemic Encephalopathy (HIE) is a critical lifelong disabling neonatal disease with insufficient effective therapies. Signaling molecules derived from astrocyte-neuron crosstalk have the potential to improve improve the prognosis, but relevant HIE research is limited. Methods: Rice-Vannucci model-induced hypoxic-ischemic brain damage (HIBD) in postnatal day 7 (P7) rat pups was confirmed by Pathological staining and laser speckle imaging. P10 whole brains underwent single-cell RNA sequencing, astrocytes after oxygen-glucose deprivation had proteomic sequencing. Multiplex immunofluorescence identified astrocyte subtypes; Enzyme-linked immunosorbent assay and Western blotting detected thyroid hormones and signaling pathways. Therapeutic efficacy was evaluated by Pathological staining and Morris Water Maze. Results: Utilizing a comprehensive single-cell transcriptomic atlas of the entire brain, this study elucidates a significant transcriptional association between astrocytes and neurons. We identified five distinct astrocyte subpopulations and characterized the Dio2⁺Slc1a2⁺subpopulation as "Metabo-neuroprotective Astrocytes" through multi-dimensional evidence. Notably, the abundance of this subpopulation was markedly diminished in the HIBD model. Pseudotime analysis further demonstrated that astrocytic proinflammatory activity is temporally regulated. Both in vivo and in vitro experiments corroborated that enhancing Dio2 expression in astrocytes or the exogenous administration of triiodothyronine (T3) can facilitate neural repair and ameliorate behavioral outcomes during both the acute and long-term phases following HIBD. Conclusions: A novel astrocyte subpopulation with neuroprotective effects was identified in the HIE model, and the temporal heterogeneity of its proinflammatory response was revealed. Meanwhile, a new crosstalk mechanism mediated by T3 shuttling between astrocytes and neurons was discovered, which can alleviate HIBD.
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Project description:Profiling of transcriptional changes in rat astrocytes when co-cultured with neurons: comparison of astrocytes cultured alone with astrocytes co-cultured with mouse hippocampal neurons. Co-cultured astrocytes are isolated using cold jet, a novel tool for these neuron-glia cultures. Over the last decade, the importance of astrocyte-neuron communication in neuronal development and synaptic plasticity has become increasingly clear. Since neuron-astrocyte interactions represent highly dynamic and reciprocal processes, we hypothesized that at least part of the involved astrocyte genes may be regulated as a consequence of their interactions with maturing neurons. In order to identify such neuron-induced astrocyte genes in vitro, we tested the effectiveness of the ‘cold jet’, a new method for separation of neurons from co-cultured astrocytes. The cold jet method is performed under ice-cold conditions and avoids protease-mediated isolation of astrocytes or time-consuming centrifugation, yielding intact astrocyte mRNA with approximately 90% of neuronal RNA removed. Using this method, we executed genome-wide profiling in which RNA derived from astrocyte-only cultures was compared with astrocyte RNA derived from differentiating neuron-astrocyte co-cultures. Data analysis revealed changes in expression of a large number of mRNAs and biological processes, including novel findings. Thus, cold jet is an efficient method to separate astrocytes from neurons in co-culture, and in this study reveals that neurons induce robust gene-expression changes in co-cultured astrocytes.
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Project description:We report that CD8+CD122+CD49dlow regulatory-like T cells (CD8+TRLs) are among the earliest lymphocytes to infiltrate mouse brain after ischemic stroke, temper inflammation, and confer neuroprotection.
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Project description:We examined the transcriptional changes modulated in ischemic brain of astrocyte specific aromatase knockout mice (GFAP-ARO-KO) by performing global transcriptome analysis.Total RNA was isolated from FLOX and GFAP-ARO-KO mice that underwent 20-minute CCA occlusion, followed by 24-hour reperfusion. The collected hippocampi samples were subjected to RNA isolation and Illumina TruSeq RNA sample preparation and sequencing was done using UT Health San Antonio genomics core facility protocol. We observed that that the ischemic GFAP-ARO-KO mouse hippocampus failed to upregulate a group of genes, which have been suggested to represent the “A2” neuroprotective signature of astrocytes. In addition, the JAK-STAT3 pathway, which is critical for the induction of reactive astrogliosis, was significantly down-regulated in the GFAP-ARO-KO hippocampus following GCI. Additional pathways that altered in GFAP-ARO-KO hippocampus were related to cytokine, chemokine and inflammatory signaling pathways.
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Project description:Protein from astrocytes (glial fibrillary acidic protein-positive cells), neurons (beta-III tubulin-positive cells), and unsorted (cell suspension without any enrichment based on astrocyte or neuron markers) from human, post-mortem Alzheimer's disease (AD) and aged-matched non-symptomatic (NS) prefrontal cortex brain samples.
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Project description:Astrocyte-Derived Estrogen Regulates Reactive Astrogliosis and is Neuroprotective Following Ischemic Brain Injury
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