Microglia Diversity in Healthy and Diseased Brain: Insights from Single-Cell Omics

Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment. This plasticity is attributed to the ability of microglia to adapt a context-specific phenotype. Numerous gene expression profiling studies of immunosorted CNS immune cells did not permit a clear dissection of their phenotypes, particularly in diseases when peripheral cells of the immune system come to play. Only recent advances in single-cell technologies allowed studying microglia at high resolution and revealed a spectrum of discrete states both under homeostatic and pathological conditions. Single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry (Cytometry by Time-Of-Flight, CyTOF) enabled determining entire transcriptomes or the simultaneous quantification of >30 cellular parameters of thousands of individual cells. Single-cell omics studies demonstrated the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies: neurodegenerative disorders, stroke, depression, and brain tumors. We summarize the findings from those studies and the current state of knowledge of functional diversity of microglia under physiological and pathological conditions. A precise definition of microglia functions and phenotypes may be essential to design future immune-modulating therapies.