Fifty Shades of Microglia

Abstract

In a recent study, Masuda and colleagues (Nature 2019;566:388-392) used single-cell RNA-sequencing (scRNA-seq) to profile microglia across different anatomical compartments, developmental stages, and types of brain pathology in mice. Moreover, the authors performed a novel transcriptomic characterization of microglia from multiple sclerosis patients and identified phenotypically conserved microglial subsets between species. These findings, together with seminal prior results from various groups, provide valuable insights into the spatiotemporal heterogeneity of microglia during brain development and disease.

Keywords: cuprizone model; facial nerve axotomy; microglial transcriptomic signature; mouse and human microglia; multiple sclerosis; single-cell RNA sequencing.

Figure 1

a) Embryonic mouse microglia are Tmem119-negative and are enriched for genes associated with lysosomal function and apolipoproteins. b) Adult mouse microglia under healthy condition are characterized by higher expression of homeostatic signature genes (such as Tmem119, Selplg, Cst3, Sparc and the long non-coding RNA Malat1). c) During disease, mouse microglia downregulate homeostatic signature genes, whereas a specific set of genes is transiently upregulated depending on the pathological context. Once the lesion is resolved, microglia recover the homeostatic gene signature, though the recovery rate is dependent on type of injury (e.g., focal degeneration of the facial nucleus or toxic demyelination in the corpus callosum). d) Human microglia are a heterogeneous population, distinguished by signature genes like Tmem119, Cx3cr1, Cst3, etc. e) In MS patients, some microglia resemble the homeostatic phenotype of the healthy brain (homeostatic-like subset), whereas others are specific of the MS brain and are enriched for genes associated with inflammation and tissue damage (inflammatory subsets).