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Immunity. 2019 Jan 15;50(1):253-271.e6. doi: 10.1016/j.immuni.2018.11.004. Epub 2018 Nov 21.

Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.

Author information

1
Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2
Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA.
3
Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Division of Newborn Medicine, Department of Medicine, Boston, MA, USA.
4
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
5
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
7
Singapore Immunology Network (SIgN), A(∗)STAR, Biopolis, Singapore.
8
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address: mccarroll@genetics.med.harvard.edu.
9
Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. Electronic address: beth.stevens@childrens.harvard.edu.

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. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our 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 multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.

KEYWORDS:

activation; brain; demyelination; development; diversity; glia; heterogeneity; injury; microglia; single-cell RNA seq

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