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Excitotoxic glutamate levels drive spinal cord ependymal stem cell proliferation and fate specification through CP-AMPAR signaling.

ABSTRACT: 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.

SUBMITTER: Hachem LD

PROVIDER: S-EPMC10031285 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Excitotoxic glutamate levels drive spinal cord ependymal stem cell proliferation and fate specification through CP-AMPAR signaling.

Hachem Laureen D LD Hong James J Velumian Alexander A Mothe Andrea J AJ Tator Charles H CH Fehlings Michael G MG

Stem cell reports 20230209 3

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 ...[more]

PMID: 36764296

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Dataset Information

Excitotoxic glutamate levels drive spinal cord ependymal stem cell proliferation and fate specification through CP-AMPAR signaling.

Publications

Excitotoxic glutamate levels drive spinal cord ependymal stem cell proliferation and fate specification through CP-AMPAR signaling.

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