Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1,2,3,4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.
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Raw data for mouse and human single cell RNA-sequencing have been deposited in the Gene Expression Omnibus, and are available at the following accession numbers: GSE120629 (mouse), GSE120747 (mouse) and GSE124335 (human). All other data are available from the corresponding author on reasonable request.
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We thank M. Ditter, E. Barleon, T. el Gaz and J. Bodinek-Wersing for technical assistance; C. Gross for proofreading; N. Mossadegh for helpful discussions; and A. Zeisel and S. Linnarsson (Karolinska Institute, Sweden) for sharing data and support. The samples and data used for this project were kindly provided by the West German Biobank. T.M. was supported by the KANAE Foundation and the Japan Society for the Promotion of Science. M.P. is supported by the Sobek Foundation, the Ernst-Jung Foundation, the DFG (SFB 992, SFB1160, SFB/TRR167, Reinhart Koselleck Grant), the Ministry of Science, Research and Arts, Baden-Wuerttemberg (Sonderlinie ‘Neuroinflammation’) and the BMBF-funded competence network of multiple sclerosis (KKNMS). This study was supported by the DFG under Germany’s Excellence Strategy (CIBSS – EXC-2189 – Project ID390939984). J.P. is supported by the DFG (SFB/TRR167 B05 and B07), BIH CRG 2a, and the UK DRI Momentum Award. C. Stadelmann is supported by the DFG (STA1389/2-1), the Deutsche Multiple Sklerose Gesellschaft (DMSG), the National MS Society of the USA (NMSS) and the Hertie Foundation. C.B. is supported by the DFG (SFB/TRR167 B05).
Nature thanks Arnold Kriegstein and the other anonymous reviewer(s) for their contribution to the peer review of this work.