ABSTRACT
Microglia are brain immune cells that constantly survey their environment to maintain homeostasis. Enhanced microglial reactivity and proliferation are typical hallmarks of neurodegenerative diseases. Whether specific disease-linked microglial subsets exist during the entire course of neurodegeneration, including the recovery phase, is currently unclear. Taking a single-cell RNA-sequencing approach in a susceptibility gene-free model of nerve injury, we identified a microglial subpopulation that upon acute neurodegeneration shares a conserved gene regulatory profile compared to previously reported chronic and destructive neurodegeneration transgenic mouse models. Our data also revealed rapid shifts in gene regulation that defined microglial subsets at peak and resolution of neurodegeneration. Finally, our discovery of a unique transient microglial subpopulation at the onset of recovery may provide novel targets for modulating microglia-mediated restoration of brain health.
Subject(s)
Cytokines/metabolism , Microglia/metabolism , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/physiopathology , Recovery of Function/physiology , Sequence Analysis, RNA/methods , Animals , Axotomy/methods , CX3C Chemokine Receptor 1/genetics , CX3C Chemokine Receptor 1/metabolism , Calcium-Binding Proteins/metabolism , Disease Models, Animal , Facial Nerve Injuries/complications , Gene Expression Profiling , Gene Expression Regulation/genetics , Glial Fibrillary Acidic Protein/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Mice , Mice, Transgenic , Microfilament Proteins/metabolism , Microglia/pathology , Neurodegenerative Diseases/etiology , Single-Cell AnalysisABSTRACT
Microglia constitute a highly specialized network of tissue-resident immune cells that is important for the control of tissue homeostasis and the resolution of diseases of the CNS. Little is known about how their spatial distribution is established and maintained in vivo. Here we establish a new multicolor fluorescence fate mapping system to monitor microglial dynamics during steady state and disease. Our findings suggest that microglia establish a dense network with regional differences, and the high regional turnover rates found challenge the universal concept of microglial longevity. Microglial self-renewal under steady state conditions constitutes a stochastic process. During pathology this randomness shifts to selected clonal microglial expansion. In the resolution phase, excess disease-associated microglia are removed by a dual mechanism of cell egress and apoptosis to re-establish the stable microglial network. This study unravels the dynamic yet discrete self-organization of mature microglia in the healthy and diseased CNS.