Astrocyte-driven multicellular mechanisms of CNS repair and cerebroprotection

Astrocytes are central regulators of brain homeostasis, which respond dynamically to injury and disease by modulating neuronal activity, immune responses, and vascular function. Recent work has revealed that the diversity of astrocytic states and their context-dependent interactions with neighboring cells critically influence outcomes after central nervous system (CNS) injury and inflammation. This review synthesizes new insights into how astrocytes interact with microglia, neurons, and the neurovascular unit to shape neuroprotection and repair. We discuss how astrocyte-secreted proteins dynamically regulate synaptic remodeling following stroke; how regionally restricted lesion-remote astrocytes govern the specification of repair-associated microglia and promote white matter regeneration after trauma; and how signaling between astrocytes and microglia modulates neuronal survival in neurodegeneration. We further highlight emerging evidence linking disrupted astrocyte-endothelial cell interactions to neurodegenerative disease in humans. Together, these findings illustrate that astrocyte heterogeneity and multicellular communication define the balance between injury resolution and degeneration. Understanding these multidimensional astrocytic networks opens new avenues for therapeutic strategies aimed at promoting neuroprotection, restoring circuit function, and minimizing long-term neurological deficits.