Abstract: Harmful and helpful roles of astrocytes in spinal cord injury (SCI): SCI induce gradable sensory, motor and autonomic impairments that correlate with the lesion severity and the rostro-caudal location of the injury site. The absence of spontaneous axonal regeneration after injury results from neuron-intrinsic and neuron-extrinsic parameters. Indeed, not only adult neurons display limited capability to regrow axons but also the injury environment contains inhibitors to axonal regeneration and a lack of growth-promoting factors. Amongst other cell populations that respond to the lesion, reactive astrocytes were first considered as only detrimental to spontaneous axonal regeneration. Indeed, astrocytes, that form the outer layer of the glial scar, play a predominant mechanical role as a barrier to axonal regeneration. However, evidence also attests to the beneficial functions of astrocytes after SCI. For instance, the glial scar barrier also limits the spread of inflammation and the extension of the lesion. Following SCI, astrocytes undertake significant molecular changes. We have earlier identified in mice that approximately 10% of resident mature astrocytes located in the vicinity of the lesion site naturally transdifferentiate into a neuronal phenotype (Noristani et al., 2016). Besides, SCI-induced converted astrocytes display an augmented expression of a neural stem cell marker, fibroblast growth factor receptor 4 (Fgfr4) (Noristani et al., 2016). FGFR (including FGFR4) is crucial during neuronal differentiation and FGF4, a ligand of FGFR4, is essential for astrocyte dedifferentiation into neural stem cells. Thus we recently, investigated whether increasing SCI-induced Fgfr4-upregulation within astrocytes may improve recovery and tissue preservation (Bringuier et al., 2023). We first showed an increased βIII-tubulin expression in astrocytes resulting from lentiviral-mediated astrocytic Fgfr4 over-expression. RNAseq analysis of converted astrocytes (astrocytes expressing βIII-tubulin) revealed a concomitant upregulation of neurogenic pathways and downregulation of Notch signaling. Both mechanisms are consistent with astrocyte-to-neuron conversion. Second, using open field and CatWalk® behavioral analysis, we highlighted that the enhancement of Fgfr4 specifically in astrocytes just after a lateral hemisection of the spinal cord improves motor recovery in mice. Interestingly, we observed that Fgfr4 over-expression-induced improvements are sex-dependent for fine motricity. We also observed a better gross motor function recovery in females as compared to males. This sexually dimorphic response correlates with a decrease in lesion volume in females conversely to males. We then concentrated our histological investigations on females only and we show that caudal to the lesion, Fgfr4 over-expression preserves myelin and reduces glial reactivity (Bringuier et al., 2023).