Transcriptome analysis of the course of ischemic stroke from acute to chronic phase in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279665 | GEO | 2026/02/20
REPOSITORIES: GEO
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Project description:We conducted an examination of alterations in gene expression in the ischemic brain of mice at 3 and 14 days after cerebral infarction, in comparison to the control and sham operation groups at single nucleus-transcriptomic levels. By cell type annotation, we obtained neurons (glutamatergic and GABAergic), fibroblast-like cells, astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes, microglia, endothelial cells, and pericytes. We observed survival signals in neurons in addition to extensive inflammatory changes and neuronal death signals. A massive change was observed on day3, showing the loss of glutamatergic neuron and the increase of endothelial cells. This tendency was slightly recovered towards day14. Our findings revealed elevated expression of autophagy and cAMP signaling in surviving neurons within the penumbra region.
2026-02-20 | GSE279666 | GEO
Project description:Increasing evidence shows that brain pericytes can acquire multipotency to produce multi-lineage cells following injury. However, pericytes are a heterogenous population and it remains unknown whether there are different potencies from different subsets of pericytes in response to injury. Here, using single-cell RNA-sequencing (scRNA-seq) and immunohistochemistry analysis following ischemic stroke, we showed that NG2+ pericyte subset expressed very strong neural reprogramming potential to produce newborn neurons, while Tbx18+ pericytes displayed strong multipotency to produce endothelial cells, fibroblasts, and microglia but with minimal neural reprogramming potency. In addition, we mimicked ischemic stroke in vitro and developed an NG2+ pericyte neural reprogramming culture model. Here we discovered that AMP-dependent kinase (AMPK) modulators facilitated pericyte to neuron conversion by modulating Ser436 phosphorylation status of CREB-binding protein (Cbp), a histone acetyltransferase, which coordinated an acetylation shift between the non-histone substrate (Sox2) and the histone substrate (H2B) and modulated Sox2 nuclear-cytoplasmic trafficking during reprogramming/differentiation process. Finally, we identified that sequential treatment of compound C (CpdC) and metformin, AMPK inhibitor and activator respectively through reprogramming/differentiation process, robustly facilitated the conversion of human pericyte into functional neurons via transient pericyte-derived neural stem cell population.
2024-10-01 | GSE250597 | GEO
Project description:The current treatment options for ischemic stroke aim to achieve reperfusion but are time critical. Novel therapeutic approaches that can be given beyond the limited time window of 3 - 4.5 hours are still an unmet need to be addressed to improve stroke outcome. The lack of oxygen and glucose in the area of ischemic injury initiates a pathological cascade leading to blood-brain barrier (BBB) breakdown, inflammation and neuronal cell death, a process that may be intercepted to limit stroke progression. Pericytes located at the blood/brain interface are one of the first responders to hypoxia in stroke and therefore a potential target cell for early stroke interventions. Using single-cell RNA sequencing in a mouse model of permanent middle cerebral artery occlusion, we investigated the temporal differences in transcriptomic signatures in pericytes at 1, 12, and 24 hours after stroke compared to the contralateral hemisphere. Our results reveal a stroke-specific subcluster of pericytes that is present at 12 and 24 hours and characterized by the upregulation of genes mainly related to cytokine signalling and immune response. This study identifies temporal transcriptional changes in the acute phase of ischemic stroke that reflect the early response of pericytes to the ischemic insult and its secondary consequences and may constitute potential future therapeutic targets.
2023-06-29 | GSE234052 | GEO
Project description:The mammalian adult brain contains two neural stem and precursor (NPC) niches: subventricular zone [SVZ] lining the lateral ventricles and subgranular zone [SGZ] in the hippocampus. From these SVZ NPCs represent the largest NPC pool. Notably, while SGZ NPCs typically only produce neurons and astrocytes, SVZ NPCs produce neurons, astrocytes and oligodendrocytes throughout life. Of particular importance is the generation and replacement of oligodendrocytes, the only myelinating cells of the central nervous system (CNS). SVZ NPCs contribute to myelination by regenerating oligodendrocyte precursor cell (OPC) pool and by differentiating into oligodendrocytes in the developing and demyelinated brain. The neurosphere assay has been widely adopted by the scientific community to facilitate the study of NPCs in vitro. Here, we present a streamlined protocol for culturing postnatal and adult SVZ NPCs and OPCs from primary neurosphere cells. We characterize the purity and differentiation potential as well as provide RNA-sequencing profiles of postnatal SVZ NPCs, postnatal SVZ OPCs and adult SVZ NPCs. We show that primary neurospheres cells generated from postnatal and adult SVZ differentiate into neurons, astrocytes and oligodendrocytes concurrently and at comparable levels. SVZ OPCs are generated by subjecting primary neurosphere cells to OPC growth factors fibroblast growth factor (FGF) and platelet-derived growth factor-AA (PDGF-AA). We further show SVZ OPCs can differentiate into oligodendrocytes in the absence and presence of thyroid hormone T3. Transcriptomic analysis confirmed the identities of each cell population and revealed novel immune and signalling pathways expressed in an age and cell type specific manner.
2022-12-19 | GSE217507 | GEO
Project description:The mature CNS contains PDGFRA+ ‘oligodendrocyte progenitor cells’ (OPC) which may remain quiescent, proliferate, or differentiate into oligodendrocytes. In human gliomas, rapidly proliferating Olig2+ cells resembling OPCs are frequently observed. We sought to identify, in vivo, candidate pathways uniquely required for OPC differentiation or quiescence. Using the bacTRAP methodology, we generated and analyzed mouse lines for translational profiling the major cells types (including OPCs), in the normal mouse brain. We then profiled oligodendoglial (Olig2+) cells from a mouse model of Pdgf-driven glioma. This analysis confirmed that Olig2+ tumor cells are most similar to OPCs, yet, it identified differences in key progenitor genes - candidates for promotion of differentiation or quiescence. There are two datasets here. One characterizes the normal translational profiles of neurons, astrocytes, mature and immature oligodendrocytes. Each cell type was profiled in triplicate, from pools of at least two mice, and total RNA controls were collected in parallel. The second dataset includes translational profiles of Olig2 positive cells from tumors form several variations of a murine model of glioma. Each variation was collected at least in triplicate, and total RNA controls were analyzed in parallel. All translational profiles were generated using the Translating Ribosome Affinity Purification protocol.
2012-10-04 | E-GEOD-30626 | biostudies-arrayexpress
Project description:Methods: In our study, we added tdTomato gene inherent in our mouse model gene list to obtain the final matrics by modifying the reference genome. Finally, we separated the matrix by the cell type judgment result obtained by the cellranger. Cells with high quality were selected with the following criteria: (1) Genes detected in < 3 cells were removed; (2) Cells with unique molecular identified (UMI) ≤ 150 or ≥ 4500 were removed. (3) Cells with ≥ 20% mitochondrial counts were removed. Results: scRNA-seq for the cells dissociated from a CKO_NG2-CreER tumor (Figure 1B) identified 12 distinct clusters, visualized using t-distributed stochastic neighbor embedding (t-SNE). Referring to known cellular markers in the brain 24, we could identify the cell identities/states of 10 clusters, including two for OPCs (C5 and C7), two for microglia (C1 and C4), one each for astrocytes (C2), endothelial cells (C3), oligodendrocytes (C6), pericytes (C9), neurons (C11) and T/dendritic cells (C12). Projection of lineage marker tdTomato onto the t-SNE map further revealed that 4 clusters (C2, C6, C7 and C9) were likely derived from NG2-CreER labeled cells and/or their progeny Conclusions: scRNA-seq suggests that tumor OPCs in adult OPC-originated gliomas may function as TICs given their strong stemness feature.
2020-09-18 | GSE158175 | GEO
Project description:Neurons and oligodendrocytes communicate to regulate oligodendrocyte development and ensure appropriate axonal myelination. Here, we show that Glycerophosphodiester phosphodiesterase 2 (GDE2) encodes a neuronal pathway that promotes oligodendrocyte maturation through the release of soluble neuronally-derived factors. Mice lacking global or neuronal GDE2 expression have reduced mature oligodendrocytes and myelin proteins but retain normal numbers of oligodendrocyte precursor cells (OPCs). WT OPCs cultured in conditioned medium (CM) from Gde2 null (Gde2KO) neurons exhibit delayed maturation, recapitulating in vivo phenotypes. Gde2KO neurons show robust reduction in canonical Wnt signaling and genetic activation of Wnt signaling in Gde2KO neurons rescues in vivo and in vitro oligodendrocyte maturation. Phosphacan, a known stimulant of OL maturation, is reduced in CM from Gde2KOneurons but is restored when Wnt signaling is activated. These studies identify GDE2 control of Wnt signaling as a neuronal pathway that signals to oligodendroglia to promote oligodendrocyte maturation.
2021-09-09 | PXD018080 | Pride
Project description:Oligodendrocyte precursor cells (OPCs) are traditionally known for their role in differentiating into oligodendrocytes, thereby contributing to myelination. Additionally, it has been increasingly recognized that OPCs actively modify their characteristics in response to the surrounding environment, exhibiting various other functions. However, how and when OPCs change their characteristics after acute ischemic stroke, and the contribution of these changes to post-stroke recovery, are not well understood. In this study, we aimed to transcriptionally characterize the changes in OPCs during acute ischemic stroke and develop therapies to support these changes. For this purpose, we first leveraged mouse single-cell RNA sequencing (scRNAseq) datasets to create a “middle cerebral artery occlusion (MCAO) atlas.” Crucially, we identified the distinct appearance of “angiogenic” OPCs in the subacute phase and “oligogenic” OPCs in the chronic phase after MCAO, contributing to angiogenesis and remyelination, respectively. Furthermore, we successfully induced OPCs ex vivo with similar functional characteristics to “angiogenic” OPCs through severe hypoxic preconditioning. The intravenous transplantation of these hypoxia-preconditioned OPCs more efficiently promoted post-stroke angiogenesis, reduced infarct size, and improved neurological function after MCAO compared to normally treated OPCs. Finally, we demonstrated that mild hypoxia at least partially contributes to the generation of “oligogenic” OPCs. Therefore, following acute ischemic stroke, OPCs sense oxygen levels and undergo phenotypic changes to exhibit functions required at specific times. Importantly, therapies supporting these phenotypic changes hold great promise for improving recovery from damage caused by acute ischemic stroke, for which current available treatments focus on quickly restoring blood flow.
2025-11-09 | GSE275670 | GEO
Project description:Oligodendrocyte progenitor cells (OPCs) are a mitotically active population of glia that comprise approximately 5% of the adult brain. OPCs maintain their proliferative capacity and ability to differentiate in oligodendrocytes throughout adulthood, but relatively few mature oligodendrocytes are produced following developmental myelination. Recent work has begun to demonstrate that OPCs likely perform multiple functions in both homeostasis and disease, and can significantly impact behavioral phenotypes such as food intake and depressive symptoms. However, the exact mechanisms through which OPCs might influence brain function remains unclear. In this work, we demonstrate that OPCs are transcriptionally diverse and separate into three distinct populations in the homeostatic brain. These three groups show distinct transcriptional signatures and enrichment of biological processes unique to individual OPC populations. We have validated these OPC populations using multiple methods, including multiplex RNA in situ hybridization and RNA flow cytometry. This study provides an important resource that profiles the transcriptome of adult OPCs and will provide a significant foundation for further investigation into novel OPC functions.
2020-03-17 | GSE147075 | GEO
Project description:Brain pericytes are important to maintain vascular integrity of the neurovascular unit under both, physiological and ischemic conditions. Ischemic stroke is known to induce an inflammatory and hypoxic response due to the lack of oxygen and glucose in the brain tissue. How this early response to ischemia is molecularly regulated in pericytes is largely unknown but may be of importance for future therapeutic targets .Here we evaluate the transcriptional responses in in vitro cultured human brain pericytes after oxygen and/or glucose deprivation. Hypoxia has been widely known to stabilise the transcription factor hypoxia inducible factor 1-alpha (HIF1alpha) and mediate the induction of hypoxic transcriptional programs after ischemia. However, we find that the transcription factors Jun Proto-Oncogene (c-JUN), Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B-Cells (NFkappaB) and signal transducer and activator of transcription 3 (STAT3) bind genes regulated after 2 hours of omitted glucose and oxygen before HIF1alpha. Potent HIF1alpha responses require 6 hours of hypoxia to substantiate transcriptional regulation comparable to either c-JUN or STAT3. We show that STAT3 and c-JUN are regulating their bound genes before HIF1alpha after 2 hours of hypoxia or omitted glucose and oxygen, suggesting that HIF1alpha is not the initiating trans-acting factor in the response of pericytes to ischemia.
2018-03-08 | GSE109233 | GEO