The Complementary Role of Morphology in Understanding Microglial Functional Heterogeneity

Abstract

A search of the PubMed database for publications on microglia reveals an intriguing shift in scientific interest over time. Dividing microglia into categories such as “resting” and “activated” or M1 versus M2 is nowadays obsolete, with the current research focusing on unraveling microglial heterogeneity. The onset of transcriptomics, especially single-cell RNA sequencing (scRNA-seq), has profoundly reshaped our understanding of microglia heterogeneity. Conversely, microglia morphology analysis can offer important insights regarding their activation state or involvement in tissue responses. This review explores microglial heterogeneity under homeostatic conditions, developmental stages, and disease states, with a focus on integrating transcriptomic data with morphological analysis. Beyond the core gene expression profile, regional differences are observed with cerebellar microglia exhibiting a uniquely immune-vigilant profile. During development, microglia express homeostatic genes before birth, yet the bushy appearance is a characteristic that appears later on. In neurodegeneration, microglia alternate between proinflammatory and neuroprotective roles, influenced by regional factors and disease onset. Understanding these structural adaptations may help identify specific microglial subpopulations for targeted therapeutic strategies.