Repopulation of microglia and its implications for CNS disorders: Insights from the single-cell era.

Microglia, as resident macrophages in the central nervous system (CNS), have been the focus of the scientific community. The pace of exploration in the origin and development of microglia, though tortuous, never stops. Since colony-stimulating factor receptor 1 (CSF1R) inhibitors can achieve effective depletion of microglia and the repopulated microglia can be comparable to the controls, the therapeutic potential of this repopulation has prompted increasing attention and investigation. Meanwhile, single-cell sequencing technology (scRNA-seq) revealed cell fate determination and cell heterogeneity of microglia during development, homeostasis, and pathological states, identifying various functional subpopulations, including disease-associated microglia (DAM), neurodegenerative microglia (MGnD), and others. Thus, novel therapeutic values are bestowed on the repopulated microglia given their strong self-renewal capacity and highly proliferative and migratory abilities. In this paper, we first provide a comprehensive summary of the exploration process concerning the origin, development, repopulation, and heterogeneity of microglia. Moreover, we emphasize the implications of microglial repopulation in CNS disorders in the era of single-cell to enhance the understanding of microglial repopulation and provide more insights for new therapeutic strategies.