Region-specific astrocyte heterogeneity in the white matter reveals region-specific astrogenesis

Astrocyte heterogeneity has been extensively studied, but our understanding of white matter (WM) astrocytes and their distinctions from grey matter (GM) astrocytes remains limited. We directly compared astrocytes from cortical GM, WM, and the subependymal zone using scRNA-seq and spatial transcriptomics of murine forebrain sections. The comparison revealed significant differences between WM and GM astrocytes, including cytoskeletal and metabolic hallmarks specific to WM astrocytes. Furthermore, we identified two clusters of WM astrocytes, one with shared gene expression across regions and species, observed in our scRNA-seq of cerebellar WM astrocytes and human cortical WM astrocytes, highlighting a common signature across regions and species. The other cluster of WM astrocytes was region-specific and characterized by elevated expression of progenitor/proliferation genes. Functional experiments confirmed astrocyte proliferation in telencephalic WM, but not in cerebellar WM, suggesting that WM may be a novel source of adult-generated astrocytes, potentially contributing to the GM population.