Transcriptomic profile of reactive astrocytes induced by activation of the JAK2-STAT3 pathway in mouse striatal astrocytes
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PROVIDER: PRJNA420366 | ENA |
REPOSITORIES: ENA
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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
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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.
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Project description:We analyzed the transcriptional profile of striatal astrocytes from 1) Hdh140 mice infected with AAV-GFP, 2) astrocytes from Hdh140 mice infected with AAV-JAK2ca (+ AAV-GFP, at the same total virus load). We show that JAK2ca activates the JAK2-STAT3 patwhay in striatal astrocytes, induces reactive changes and activates a proteostasis signature.
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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.
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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 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.
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Project description:Glial pathology has been implicated as a causal contributor to the dysfunction and death of striatal neurons that characterizes Huntington disease. In this study, we investigated mutant HTT (mHTT)-associated changes in gene expression by both mouse and human striatal astrocytes. Mouse striatal astrocytes were FACS-sorted from two distinct models, R6/2 and zQ175 mice, which respectively express exon1-only truncated or full-length HTT, while human astrocytes were generated from either hESCs expressing full-length mHTT, or fetal striatal glia transduced with exon1-only mHTT. Comparison of differential gene expression between each of these conditions and their normal HTT controls, and to one another, revealed astrocyte-specific alterations in both truncated and full-length mHTT models that were shared by both species, yet with differences that clearly distinguished glia derived from each model. Overlap of these data sets revealed that the patterns of mHTT-associated transcriptional dysregulation depended not only upon species, but also upon whether the astroglia expressed truncated or full-length mHTT. These data revealed a common set of conserved, mHTT-associated dysregulated pathways that may present targets for the rescue of glial pathology in HD, while revealing that the gene expression of glia expressing truncated mHTT may differ substantially from that of glia expressing full-length mHTT.
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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. 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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