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Single-cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia.

ABSTRACT: Microglia are ubiquitous central nervous system (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 to compare microglial subtypes in the cortex and the spinal cord. A multi-way comparative analysis was carried out on samples from C57/BL and HIV gp120 transgenic mice at two, four, and eight months of age. The results revealed overlapping but distinct microglial populations in the cortex and the spinal cord. The differential heterogeneity of microglia in these CNS regions was further suggested by their disparity of plasticity in response to life span progression and HIV-1 pathogenic protein gp120. Our findings indicate that microglia in different CNS compartments are adapted to their local environments to fulfill region-specific biological functions.

SUBMITTER: Zheng J

PROVIDER: S-EPMC7921843 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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Single-cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia.

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