Astrocyte regeneration via FGF8-DBX1 signalling facilitates recovery in neuromyelitis optica rats

Astrocytes are the most abundant glial cells supporting neuronal function. The subtypes and spatial distribution of astrocytes in the spinal cord are determined by their progenitor domains, and they are not replenished beyond their original distribution. However, under pathological conditions with a severe loss of astrocytes such as neuromyelitis optica (NMO), the underlying mechanism of astrocyte regeneration and how they regenerate over the original domain remains unknown. In the present study, we developed an acute severe NMO rat model that showed extensive loss of astrocytes in the spinal cord, and observed marked astrocyte regeneration from cells around the central canal. Using an in vitro screening system and subsequent in vivo analysis, we identified fibroblast growth factor 8 (FGF8) as a strong activator of astrocyte regeneration. Notably, FGF8 stimulates astrocyte regeneration via developing brain homeobox 1 (Dbx1), which is one of the determinants of astrocyte distribution during development. Interestingly, regenerating astrocytes positive for Dbx1 spread beyond the original domain, suggesting that the intrinsic limitation of regional specificity of astrocytes disappears under pathological conditions in adults. We further revealed that the FGF8-induced enhancement of astrocyte regeneration promoted neuronal circuit reorganization and functional recovery. Our findings provide a fundamental understanding of astrocyte regeneration after central nervous system damage and suggest the FGF8-Dbx1 axis as a novel therapeutic target.