Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain

Abstract

Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. In this study, we analyzed the RNA expression patterns of more than 76,000 individual microglia during development, old age and after brain injury. Analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states - including chemokine-enriched inflammatory microglia - persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human MS lesions. These unique microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

“…The phenotype of microglia is highly plastic (Ransohoff & El Khoury, 2015). Microglia alter their gene expression in development and in models of demyelination and neurodegeneration (Bedard, Tremblay, Chernomoretz, & Vallieres, 2007;Gao et al, 2017;Hammond et al, 2018;Hirbec, Noristani, & Perrin, 2017;Li et al, 2018). The precise effects of rCSF1 onto CC microglia remain an open question.…”

The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease

“…This finding is further supported by evidence from AD cases demonstrating that microglial density is proportional to neurofibrillary tangle frequency and distribution (94). In addition, TMEM119 has been shown to be stably and selectively expressed in adult microglia (9, 95), and appears to exhibit stable expression even in response to a variety of inflammatory conditions (9, 96). Taking all of the above into consideration, it would be tempting to speculate that the expression changes we observed in this study are primarily a reflection of microglial cellularity.…”

“…Several publications within the last 2 years have begun to employ scRNAseq and mass cytometry of microglia and other CNS immune cells as ways to understand (i) global alterations in immunological gene expression and (ii) dynamic changes in immune cell-type abundance as a function of brain anatomy, aging, and neurodegeneration (87, 95, 107, 108). The major advantage of these techniques is that they enable unbiased, global profiling of gene expression uninfluenced by changes in cellularity, as well as characterization of cell-type fluctuations as a function of anatomy, age, and disease.…”

Modern approaches to investigating non‐neuronal aspects of Alzheimer's disease

“…It will be increasingly interesting to discover if these (probable) disease-associated transcripts are isolated to particular subsets of individual CNS cells. As such single-cell databases are currently released on a routine basis, this will surely be evident soon (29)(30)(31)(32)(33). How does Figure 1.…”