RNA-Seq analyses of glial cells reveal astrocyte-toneuron conversion induced by spinal cord injury

Orateur : Florence PERRIN (Université Montpellier)

Spinal cord injury (SCI) prompts pronounced glial reactivity including proliferation and migration of astrocytes and microglia toward the site of lesion that participate to the formation of a glial scar. SCI-induced astrogliosis is mainly regarded as detrimental for successful axonal regeneration, however, molecular changes in astrocytes can also exert beneficial effects. We have recently studied transcriptomic alterations (using RNAsequencing) in astrocytes and microglia at different stages after SCI to unveil the molecular signature of injuries-induced gliosis. We demonstrated the heterogeneity of astrocytic response and identified the induction of the neural stem cell lineage and the over-expression of the neuronal progenitor gene βIII-tubulin specifically in astrocytes. The sub-population of astrocytes expressing βIIItubulin also displayed morphological changes from typical stellate shape to classical neuronal progenitor. We observed that it is the resident mature astrocytes, rather than newly formed astrocytes, that undergo transdifferentiation towards neuronal lineage. We then identified that transdifferentiating astrocytes eventually express GABAergic, but not glutamatergic, markers. Besides, we identified the induction of the fibroblast growth factor receptor 4 (Fgfr4) as a potential player responsible for SCI-induced astrocytic transdifferentiation towards neuronal lineage. Indeed, Fgfr4, that is known to promote embryonic stem cell differentiation towards neuronal lineage, showed pronounced over-expression from 72 hours to 6 weeks following lesion. We thus show that resident astrocytes have an intrinsic capacity to undergo injuryinduced transdifferentiation towards neuronal lineage. Stimulating this intrinsic pathway may provide a new therapeutic strategy to replace lost neurons and improve functional outcomes after SCI.

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