Gene expression-based, astrocyte treatments
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ABSTRACT:
PROVIDER: PRJNA746565 | ENA |
REPOSITORIES: ENA
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Project description:Astrocytes, a major cell type found throughout the central nervous system have general roles in neuronal development, blood-brain barrier function, regulation of neuroimmune responses as well as metabolic support of other brain resident cells. Here we show that a distinct subtype of reactive astrocyte is induced by activated endothelial cells and is distinct from astrocytes classically activated by neuroinflammatory microglia. We show that activated endothelial cells strongly induce C3 + astrocytes that retain their phagocytic capacity while exhibiting a gain of neurotoxic function decreasing neuronal cell survival. We show that endothelial activated astrocytes have increased A1-astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we show that endothelial activated astrocytes are Decorin positive and are associated to vascular amyloid deposits but not amyloid plaques in mouse models and AD/CAA patients. Taken together these findings show the existence of potentially extensive and subtle functional diversity of A1-reactive astrocytes. Astrocytes treated with Control or Activated Microglia or Endothelial Conditioned media
2022-03-18 | GSE180106 | GEO
Project description:1.1 To collect pathological tumor specimens of patients with metastatic colorectal cancer in a prospective fashion for correlative studies of response to an oxaliplatin based chemotherapy regimen.
1.2 To determine a gene expression profile that predicts response to an oxaliplatin based chemotherapy regimen in this cohort of patients.
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Project description:Chromosomes and genes are non-randomly arranged within the mammalian cell nucleus. Clustering of genes is of great significance in transcriptional regulation. However, the relevance of gene clustering in their expression during differentiation of neural precursor cells (NPCs) into astrocytes remains unclear. We performed a genome-wide enhanced circular chromosomal conformation capture (e4C) to screen genes associated with an astrocyte-specific gene, glial fibrillary acidic protein (Gfap), during astrocyte differentiation. We identified 13 genes that were specifically associated with Gfap and expressed in NPC-derived astrocytes. These results provide evidence for functional significance of gene clustering in transcriptional regulation during NPCs differentiation. comparison of NPCs vs LIF+ vs LIF- cells.
2015-02-20 | E-GEOD-66097 | biostudies-arrayexpress
Project description:Primary outcome(s): Gene expression of targeted genes
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Project description:SPEACC-seq is a novel high-throughput method which enables forward genetic screens to identify cell-cell interaction mechanisms that uncovered an astrocyte-microglia regulatory circuit mediated by amphiregulin and IL33-ST2. signaling. Cell-cell interactions in the central nervous system (CNS) play central roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. For example, several factors mediate microglia-astrocyte interactions that promote CNS pathology, but less is known about regulatory interactions that limit tissue pathology. Here we report the development of SPEACC-seq (Stimulation, Perturbation, and Encapsulation of interACting Cells followed by Sequencing), a forward genetic screening platform which combines genome-wide CRISPR/Cas9 perturbations, cell co-culture in picoliter droplets, and microfluidic-based fluorescence activated droplet sorting to identify mechanisms of cell-cell communication. Using SPEACC-seq in combination with an in vivo perturb-seq screen, we identified microglia-produced amphiregulin as a suppressor of disease promoting astrocyte responses in experimental autoimmune encephalomyelitis (EAE), a pre-clinical model of multiple sclerosis (MS). The production of microglial amphiregulin was induced via ST2 signaling by IL-33 released from astrocytes during EAE. Indeed, the genetic inactivation of ST2 or amphiregulin in microglia, or IL-33 or amphiregulin signaling in astrocytes resulted in the worsening of EAE, suggesting that IL-33-induced microglial amphiregulin limits disease-promoting astrocyte responses associated with CNS pathology. This regulatory loop was also detected in human astrocytes and microglia both in vitro and in MS patient CNS samples. In summary, we developed SPEACC-seq, a high-throughput, droplet-based forward genetic screening platform for the identification of cell-cell interaction mechanisms, which identified a novel microglia-astrocyte negative feedback loop that limits CNS pathology.
2023-11-23 | GSE218732 | 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:Droplet-based forward genetic screening of astrocyte-microglia communication mechanisms
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Project description:Lineage development is a step-wise process, governed by stage-specific regulatory factors and associated markers. Astrocytes are one of the principle cell types in the CNS and the stages associated with their development remain very poorly defined. To identify these stages we performed gene expression profiling on astrocyte precursor populations in the spinal cord, identifying distinct patterns of gene induction during their development. Validation studies identified a new cohort of astrocyte-associated genes during development and demonstrated their expression in reactive astrocytes in human white matter injury (WMI).
2016-12-16 | GSE80826 | GEO