The interaction between microglia and astrocytes exhibits a relatively balanced state in order to maintain homeostasis in the healthy central nervous system (CNS). Disease stimuli alter microglia–astrocyte interaction patterns and elicit cell-type-specific responses, resulting in their contribution to various pathological processes. Here, we review the similarities and differences in the activation modes between microglia and astrocytes in various scenarios, encompassing different stages of neural development and a wide range of neural disorders. The aim is to provide a comprehensive understanding of their roles in neural development and regeneration and guiding new strategies for restoring CNS homeostasis.

Specific niche signals play a vital role in supporting the proliferation and differentiation of neural stem cells (NSCs) throughout neural development and neural regeneration. Glial cells, including astrocytes and microglia, are key components of the stem cell niche. However, their interactions with NSCs remain poorly understood. To explore these interactions, primary NSCs isolated from rat embryos were cultured in either glial cell-derived conditioned medium (CM) or co-cultured with mixed glial cells via Transwell inserts. NSC viability, proliferation, differentiation, and the underlying mechanism involving BMP4 signaling were evaluated. Results showed that microglia and astrocytes were closely localized with NSCs in the subventricular zone (SVZ) of rat brains at postnatal day 14. After being cultured with CM or glial co-culture, NSC viability and astrocytic differentiation were significantly enhanced, while cell proliferation and neuronal differentiation were reduced. BMP4 secretion by both astrocytes and microglia as well as Smad1/5/8 and Stat3 phosphorylation in NSCs was also elevated, indicating that the BMP4–Smad1/5/8 signaling pathway was involved in the effects of the glial cell niche on NSC behaviors. These findings suggest that glial cells regulate NSCs’ fate through BMP4-mediated signaling, providing potential targets for future therapeutic strategies in neurogenesis and regeneration.