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Augmenting AMPA receptor signaling following spinal cord injury increases ependymal-derived stem/progenitor cell (epNSPC) migration and promotes functional recovery

ABSTRACT: Using lineage tracing in adult mice, we demonstrate that pharmacological blockade of AMPARs reduces epNSPC proliferation and migration after cervical SCI. Similarly, knocking out AMPAR subunits in Foxj1+ ependymal cells and their progeny abolishes glutamate-mediated AMPA currents and impairs the migration of epNSPCs after SCI. Augmenting AMPAR signaling with ampakines maintains the acute maturation reversal of epNSPCs into the chronic injury period, enhances ependymal-glial cell contacts, which may contribute to the spatial distribution and migratory pattern of activated ependymal cells, ameliorates the decrease in corticospinal tract excitability subacutely after SCI, and improves long-term neurobehavioral recovery. Together this work uncovers a neurotransmitter receptor-dependent mechanism of epNSPC activation following injury, which may be targeted to harness the regenerative potential of the spinal cord.

ORGANISM(S): Mus musculus

PROVIDER: GSE295949 | GEO | 2025/10/31

REPOSITORIES: GEO

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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.

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Augmenting AMPA receptor signaling following spinal cord injury increases ependymal-derived stem/progenitor cell (epNSPC) migration and promotes functional recovery

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