Exosome-transmitted RVT1 from reactive astrocytes promotes recurrence glioblastoma proliferation
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ABSTRACT:
PROVIDER: PRJNA475107 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma (GBM) remains among the most lethal brain tumors despite improvements in treatment. Surgical resection is a universal component of glioma therapy. However, the mechanism underlying postoperative recurrence remains a challenge due to limited information regarding the changes that occur in the postoperative microenvironment. Here, we show that a subtype of proinflammatory reactive astrocytes designated is induced by inflammatory cytokines or injury. We show that reactive astrocytes can secrete the long noncoding RNA (lncRNA) LOC646762 to promotes recurrence glioblastoma proliferation in an exosome-dependent manner.We firstly named this reactive astrocyte associated lnRNA as “lnc-RVT1”.
2018-06-08 | GSE115459 | GEO
Project description:Senescence was recently linked to neurodegeneration. Senescent as well as reactive astrocytes were detected in Parkinson’s disease postmortem brains. This study aimed to determine differences and similarities between senescent and reactive astrocytes. Astrocytes were treated with the stressors hydrogen peroxide or rotenone to induce senescence or with the cytokines TNFa+IL1a or with IL1b to induce reactivity in astrocytes. Comparing the transcriptome of senescent and reactive astrocytes revealed a set of genes specific to senescent astrocytes together with genes regulated in a similar way in both astrocyte states.
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Project description:Reactive astrocytes are implicated in amyotrophic lateral sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human iPSC-derived astrocytes carrying VCP, C9orf72 and SOD1 ALS-causing mutations as well as astrocytes stimulated to undergo reactive transformation. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell-adhesion, stress-response, and immune-activation. We examined translatome sequencing (TRAP-seq) of astrocytes from a SOD1 mouse model, which revealed that transcripts upregulated in translation significantly overlap with transcripts with decreased IR. Using nucleo-cytoplasmic fractionation of VCP astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear-detained transcripts is associated with increased cytoplasmic expression of genes and proteins encoding regulators of reactivity - indicating nuclear-to-cytoplasmic translocation and translation of spliced reactivity-related transcripts. Our study provides important insights into the molecular regulation of reactive transformation of ALS astrocytes.
2021-09-09 | PXD022604 | Pride
Project description:Reactive astrocytes are implicated in Amyotrophic Lateral Sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human induced pluripotent stem cell (hiPSC)-derived astrocytes carrying VCP, C9orf72 and SOD1 ALS-causing mutations as well as astrocytes stimulated to undergo reactive transformation. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell-adhesion, stress-response, and immune-activation. We examined astrocyte translatome sequencing (TRAP-seq) from a SOD1 mouse model, which revealed a significant number of transcripts with reduced IR in ALS are upregulated in translation. Using nucleo-cytoplasmic fractionation of VCP astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear-detained transcripts is associated with increased cytoplasmic expression of genes and proteins encoding regulators of reactivity - indicating nuclear-to-cytoplasmic translocation and translation of spliced reactivity-related transcripts. These results provide novel insights into the molecular factors controlling the reactive transformation of ALS astrocytes.
2021-10-25 | GSE160133 | GEO
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. Young adult male mice underwent middle cerebral artery occlusion (MCAO) to produce ischemic stroke or control sham surgery. Young adult mice were injected intraperitoneally with 5 mg/kg lipopolysaccharide (LPS) to produce neuroinflammation or saline for control. Astrocytes were acutely purified from control and injured brains at 1 day after injury for LPS/saline injection and 1, 3 days and 7 days after MCAO/sham surgeries.
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Project description:Astrocytes are a heterogenous population of glial cells that respond to pathological insults or injury by undergoing a profound transformation called reactivity. Reactive astrocytes exhibit distinct, context-dependent cellular, molecular, and functional states that can either help or hinder tissue homeostasis. We recently identified a subtype of reactive astrocytes in the mouse brain called interferon-responsive reactive astrocytes (IRRAs), defined by interferon-responsive genes like Igtp, Ifit3, Oasl, Mx1, Cxcl10, and Gbp2 . To further this transcriptomic definition of IRRAs, we wanted to define the proteomic changes that occur in this sub-state.
2023-03-07 | MSV000091426 | MassIVE
Project description:We analyzed the transcriptional profile of normal astrocytes and astrocytes made reactive by AAV gene transfer of a contitutive form of JAK2 (JAK2ca). We show that activation of the JAK2-STAT3 pathway by JAK2ca induces significant transcriptional changes in astrocytes, recapitulating several molecular hallmarks of reactivity
2022-06-29 | GSE107486 | GEO
Project description:Astrocytes are instrumental in both maintaining CNS homeostasis and responding to tissue injury. While astrocyte activation may be a beneficial response to acute pathologies, prolonged reactive gliosis is thought to be injurious in neurodegenerative diseases, including multiple sclerosis (MS). A major limitation of studying neurodegenerative diseases is lack of human pathological specimens obtained during the acute stages, thereby relegating research to post mortem specimens often obtained years after the initiation of pathology. Rodent reactive astrocytes have been shown to be cytotoxic to neurons and oligodendrocytes but may differ from human cells, especially in diseases with known genetic susceptibility. Herein, we purified human CD49f+ astrocytes from differentiated induced pluripotent stem cells derived from individual patient and control peripheral white blood cell samples. We compared TNF and IL1a stimulated human reactive astrocytes from 7 persons with MS and 6 non-MS controls and show their specific astrocyte transcriptomic profiles are remarkably similar to those described in rodents. The functional effect of astrocyte conditioned media (ACM) was examined in a human oligodendrocyte precursor cell (OPC) line differentiation assay using a transgenic secreted reporter of myelin basic protein (MBP) expression. ACM was not cytotoxic to the OPCs but robustly inhibited the MBP reporter. No differences were seen between MS and control stimulated astrocytes at either the transcript level or in functional OPC suppression assays. We next used RNAseq to interrogate differentially expressed genes in the OPC lines that had suppressed differentiation from the human ACM. Remarkably, not only was OPC differentiation and myelin gene expression suppressed, but we observed induction of several immune pathways and Nf-κB signaling in OPCs exposed to the ACM. These data support the notion that reactive astrocytes can inhibit OPC differentiation thereby limiting their remyelination capacity, and that OPCs take on an immune profile in the context of inflammatory cues.
2022-02-14 | GSE196575 | GEO
Project description:The brain microenvironment imposes a particularly intense selective pressure on metastasis initiating cells, but successful metastasis bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment, as they have been observed to confine brain metastasis without infiltrating the lesion. We describe a subpopulation of reactive astrocytes surrounding metastatic lesions that are characterized by the activation of STAT3 pathway. Blocking STAT3 signaling in this subpopulation of reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We conclude that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by STAT3 in a subpopulation of reactive astrocytes. We also show that a safe and orally bioavailable treatment that inhibits STAT3 in patients with established brain metastasis and extracranial disease exhibits significant antitumor effects, especially in the CNS where several complete responses were achieved. Given that brain metastasis imposes significant morbidity and mortality, our experimental results suggest a novel treatment for increasing survival in patients with secondary brain tumors.
2018-07-16 | PXD008956 | Pride
Project description:Abnormal lipid accumulation have been reported in patients with temporal lobe epilepsy (TLE) by in vivo magnetic resonance imaging (MRI). However, the role of astrocytes in the regulation of neuronal activity or lipid metabolism in epilepsy is unclear. Using single-nucleus RNA sequencing of TLE patient samples, we found lipid accumulation and lipid metabolism dysfunction mainly take place in astrocytes. Mechanistic studies revealed that apolipoprotein E (APOE) mediates lipid transfer from hyperactive neurons to astrocytes, turning them into the neurotoxic reactive phenotype
2023-02-08 | GSE197015 | GEO