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Characterisation of young, old and old repopulating microglia in spinal cord and brain of C57BL/6 wild type male mice

ABSTRACT: To address whether, after depletion by Csf1r inhibition, microglia repopulating the CNS revert to a “younger” phenotype, we treated a group of 23 months old mice with the Csf1r inhibitor for 5 days and let microglia repopulate the central nervous system for 7 days. Young (3 months old) and old (23 months old) mice were included as controls. After the repopulation time, whole spinal cord samples and Fluorescence Activated Sorting (FACS)-sorted microglia cells from brain tissue were collected to perform bulk transcriptome (RNAseq) analysis. Analysis of whole spinal cord suggested that repopulating microglia tend to re-acquire its original aged phenotype. Gene expression in FACS-sorted microglia was then analyzed to better characterize its intrinsic phenotype after repopulation. In contrast to the whole spinal cord samples, old and old-treated replicates separated in Principal Component Analysis, suggesting that repopulating microglia displayed a different phenotype compared to old microglia.

ORGANISM(S): Mus musculus

PROVIDER: GSE122085 | GEO | 2019/08/31

REPOSITORIES: GEO

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Project description:Microglia are heterogeneous and ubiquitous CNS-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single cell RNA-seq (scRNA-seq) analysis to compare the transcriptomes of microglia in adult mouse(C57/Bl) brains and spinal cords to identify microglial subtypes in these CNS compartments.Cortical microglia from 2-month mice consisted of a predominant population of the homeostatic subtype (HOM-M) and a small population (4%) of the inflammatory subtype (IFLAM-M), while spinal microglia consisted of HOM-M and IFLAM-M subtype. Comparison of cortical and spinal microglia at 2, 4 and 8 months revealed consistently a higher composition of the IFLAM-M subtype in the spinal cord. At 8-month, cortical microglia differentiated a small new subtype with interferon response phenotypes (INF-M), while spinal microglia polarized toward a proinflammatory phenotype, as indicated by the increase of microglia expressing IL-1β. To further characterize the differential plasticity of cortical and spinal microglial heterogeneity, we determined the microglial transcriptomes from HIV-1 gp120 transgenic (Tg) mice, a model of HIV-associated neurological disorders. Compared with wild-type (Wt) cortical microglia, the gp120Tg cortical microglia had three new subtypes, with signatures of interferon I response (INF-M), cell proliferation (PLF-M), and myelination or demyelination (MYE-M) respectively; while INF-M and PLF-M subtypes presented at all ages, the MYE-M only at 4-month. In contrast, only the INF-M subtype was observed in the spinal microglia from 2-and 4-month gp120tg mice. Bioinformatic analysis of regulated molecular pathways of individual microglial subtypes indicated that gp120 more severely impaired the biological function of microglia in cortices than in the spinal cord. The results collectively reveal differential heterogeneity and plasticity of cortical and spinal microglia, and suggest functional differentiation of microglia in different CNS compartments.

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Characterisation of young, old and old repopulating microglia in spinal cord and brain of C57BL/6 wild type male mice

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