Excitotoxic glutamate levels drive spinal cord ependymal stem cell proliferation and fate specification through CP-AMPAR signaling
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ABSTRACT:
PROVIDER: PRJNA912215 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22739452.fastq.gz | Fastqsanger.gz | |||
| SRR22739452_1.fastq.gz | Fastqsanger.gz | |||
| SRR22739452_2.fastq.gz | Fastqsanger.gz | |||
| SRR22739453.fastq.gz | Fastqsanger.gz | |||
| SRR22739453_1.fastq.gz | Fastqsanger.gz |
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Project description:The adult spinal cord contains a population of ependymal-derived neural stem/progenitor cells (epNSPCs) that are normally quiescent, but are activated to proliferate, differentiate, and migrate after spinal cord injury. The mechanisms that regulate their response to injury cues, however, remain unknown. Here, we demonstrate that excitotoxic levels of glutamate promote the proliferation and astrocytic fate specification of adult spinal cord epNSPCs through CP-AMPAR signaling.
2023-02-08 | GSE220988 | GEO
Project description:The adult spinal cord contains a population of ependymal-derived neural stem/progenitor cells (epNSPCs) that are normally quiescent, but are activated to proliferate, differentiate, and migrate after spinal cord injury. The mechanisms that regulate their response to injury cues, however, remain unknown. Here, we demonstrate that excitotoxic levels of glutamate promote the proliferation and astrocytic fate specification of adult spinal cord epNSPCs. We show that glutamate-mediated calcium influx through calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (CP-AMPARs) in concert with Notch signaling increases the proliferation of epNSPCs via pCREB, and induces astrocytic differentiation through Hes1 upregulation. Furthermore, the in vivo targeting of this pathway via positive modulation of AMPARs after spinal cord injury enhances epNSPC proliferation, astrogliogenesis, neurotrophic factor production and increases neuronal survival. Our study uncovers an important mechanism by which CP-AMPARs regulate the growth and phenotype of epNSPCs, which can be targeted therapeutically to harness the regenerative potential of these cells after injury.
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Project description:After injury, mammalian spinal cords develop scars to confine the lesion and prevent further damage. However, excessive scarring can hinder neural regeneration and functional recovery. These competing actions underscore the importance of developing therapeutic strategies to dynamically modulate scar progression. Previous research on scarring has primarily focused on astrocytes, but recent evidence has suggested that ependymal cells also participate. Ependymal cells normally form the epithelial layer encasing the central canal, but they undergo massive proliferation and differentiation into astroglia following certain injuries, becoming a core scar component. However, the mechanisms regulating ependymal proliferation in vivo remain unclear. Here we uncover an endogenous κ-opioid signalling pathway that controls ependymal proliferation. Specifically, we detect expression of the κ-opioid receptor, OPRK1, in a functionally under-characterized cell type known as cerebrospinal fluid-contacting neuron (CSF-cN). We also discover a neighbouring cell population that expresses the cognate ligand prodynorphin (PDYN). Whereas κ-opioids are typically considered inhibitory, they excite CSF-cNs to inhibit ependymal proliferation. Systemic administration of a κ-antagonist enhances ependymal proliferation in uninjured spinal cords in a CSF-cN-dependent manner. Moreover, a κ-agonist impairs ependymal proliferation, scar formation and motor function following injury. Together, our data suggest a paracrine signalling pathway in which PDYN+ cells tonically release κ-opioids to stimulate CSF-cNs and suppress ependymal proliferation, revealing an endogenous mechanism and potential pharmacological strategy for modulating scarring after spinal cord injury.
2024-06-29 | GSE255883 | GEO
Project description:The spinal cord neural stem cell potential is contained within the ependymal cells lining the central canal. Ependymal cells are, however, heterogeneous and we know little about what this reflects. To gain new insights into ependymal cell heterogeneity, we microdissected the ependymal cell layer from the thoracic spinal cord of 4 FOXJ1-EGFP transgenic mice (2.5-to-3-month old). After after dissociating the tissue into a cell suspension, we sorted single GFP-positive ependymal cells into lysis plates. cDNA synthesis was performed using Smart-seq2 technology.
2022-12-13 | E-MTAB-11563 | biostudies-arrayexpress
Project description:In contrast to ependymal cells in the lateral ventricle wall (LVW), spinal cord (SC) ependymal cells possess certain neural stem cell characteristics. Isolated CD133+/CD24+/CD45-/CD34- ependymal cells from the SC displayed in vitro self renewal and differentiation capacity, whereas those from the LVW did not. The molecular basis of this difference is unknown. In this study, antibodies against multiple surface markers were applied to isolate SC and LVW ependymal cells which allowed a direct comparison of their in vitro behavior and gene expression profile. cRNA samples of three independent biological replicates of CD133+/CD24+/CD45-/CD34- LVW ependymal cells, CD133+/CD24+/CD45-/CD34- SC ependymal cells, CD133+/CD24-/CD45-/CD34- radial glial cells, and SC ependymal cell-derived NSPs were hybridized onto Illumina MouseWG-6 v1.1 gene expression arrays
2010-10-01 | E-GEOD-18528 | biostudies-arrayexpress
Project description:In contrast to ependymal cells in the lateral ventricle wall (LVW), spinal cord (SC) ependymal cells possess certain neural stem cell characteristics. Isolated CD133+/CD24+/CD45-/CD34- ependymal cells from the SC displayed in vitro self renewal and differentiation capacity, whereas those from the LVW did not. The molecular basis of this difference is unknown. In this study, antibodies against multiple surface markers were applied to isolate SC and LVW ependymal cells which allowed a direct comparison of their in vitro behavior and gene expression profile.
2010-10-01 | GSE18528 | GEO
Project description:After spinal cord injury, ependymal cells considered as stem cells activate, proliferate and differentiate mainly into glial cells. To understand this further at the molecular level, we performed RNA profiling of these cells in situ using laser-dissection and also when they are cultured as neurospheres in different conditions (growth, differentiation, dedifferentiation) Abstract: Numerous vertebrates, including Human, maintain a pool of immature cells in the ependymal region of the adult spinal cord. During injury, these ependymal cells, considered as multipotent stem cells, rapidly activate, proliferate and generate neurons and glial cells in lower vertebrates or mainly glial cells in mammals. The mechanisms underlying this activation are ill-defined and we intended to fill this gap by performing RNA profiling of mouse ependymal region after lesion. Bioinformatics and immunofluorescence identified activation of STAT3 and ERK/MAPK signaling in ependymal cells after injury. This was also accompanied by downregulation of cilia-associated genes and FoxJ1, a central transcription factor of ciliogenesis. Six genes were upregulated more than 20 fold, namely Crym, Ecm1, Ifi202b, Nupr1, Osmr, Rbp1, Thbs2 whereas only one, Acta1 was downregulated to this extent. We explored further the role and regulation in ependymal cells of Osmr, the receptor for oncostatin (OSM). This inflammatory cytokine is specifically expressed by microglia cells and we observed interactions between these cells and ependymal cells in vivo. Using culture of ependymal cells in neurospheres, we found that several cytokines induced OSMR, OSM being the most potent. OSMR is also upregulated by co-culture with OSM-expressing microglial cells. Treatment of spinal cord neural stem cells with OSM decreased their proliferation, upregulate p-Stat3 and reduced their differentiation into oligodendrocyte-lineage Olig1+ cells. These results suggest an important role for microglia-derived oncostatin in the activation and fate of spinal cord ependymal cell.
2021-04-28 | GSE149669 | GEO
Project description:The ubiquitous efflux transporter ATP-binding cassette sub-family C member 5 (ABCC5) is present at high levels in the blood-brain barrier, neurons and glia, but its in vivo substrates and function are not known. Untargeted metabolomic screens revealed that Abcc5-/- mice accumulate endogenous glutamate conjugates and analogs in several tissues, but brain in particular. The abundant neurotransmitter N-acetylaspartylglutamate (NAAG), for example, was over 2-fold higher in Abcc5-/- brain. In line with ABCC5-mediated transport, the metabolites that accumulated in Abcc5-/- tissues were depleted in cultured cells that overexpressed human ABCC5. Using membrane vesicles, we show that ABCC5 not only transports the metabolites detected in our screen, but also a wide range of peptides containing a C-terminal glutamate. Glutamate conjugates are of physiological relevance because they can affect the function of glutamate, the principal excitatory neurotransmitter in the brain. We found that ABCC5 also transports exogenous glutamate analogs, like the classic excitotoxic neurotoxins kainic acid, domoic acid and N-methyl-D-aspartate (NMDA) and the therapeutic glutamate analog ZJ43. Taken together, we have identified ABCC5 as a general glutamate conjugate and analog transporter that affects the disposition of endogenous metabolites, toxins and drugs.
2015-10-01 | GSE68628 | GEO
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