Focal astrocyte loss reveals nuclear translocation during lesion repopulation

Astrocyte loss occurs in various neurological conditions and can disrupt local tissue homeostasis. While astrocytes surrounding border-forming lesions adopt reactive states without restoring astrocyte networks, how astrocytes respond to spatially confined astrocyte loss remains poorly understood. Here we used longitudinal in vivo two-photon microscopy, combined with spatiotemporal transcriptional profiling, to examine astrocyte responses following focal aquaporin-4 antibody-mediated ablation in the somatosensory cortex of adult mouse brain, a model of astrocytopathy relevant to neuromyelitis optica spectrum disorder. Here we show that perilesional astrocytes undergo pronounced structural remodeling during lesion repopulation, characterized by cell proliferation, prolonged multinucleated astrocyte states, polarized process extension into the depleted area and gradual displacement of nuclei into previously unoccupied astrocyte territories. Spatial transcriptomics reveal an injury-associated molecular response that resolves as the astrocyte network is restored. Together, our findings delineate the spatiotemporal dynamics of astrocyte regeneration after astrocyte loss, extending current understanding of astroglial plasticity in the adult brain.