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Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes

ABSTRACT: Microglia are brain-resident, myelin-phagocytosing cells, yet their role in lesion initiation in grey and white matter regions in multiple sclerosis (MS) is unclear. We isolated primary microglia from both, occipital cortex and corpus callosum, of 10 MS and 11 control donors and studied their transcriptional profile by RNA sequencing, thereby identifying regional and MS-associated changes. Identification of pathways underlying regional differences showed a relatively increased type I interferon response in cortical grey matter microglia, while white matter microglia more highly expressed NF-κB pathway genes. In normal-appearing white matter MS tissue, lipid metabolism genes were increased, suggesting processing of myelin by microglia already in areas seemingly devoid of MS pathology. Normal-appearing grey matter MS microglia showed increased activation of glycolysis and metal ion homeostasis, possibly reflecting microglia reacting to iron depositions. Notably, expression of genes associated with microglia homeostasis were hardly changed, suggesting that subtle regional changes in MS-associated microglia do not yet affect their resting state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111972 | GEO | 2019/03/13

REPOSITORIES: GEO

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Project description:Increasing evidence indicates heterogeneity in functional and molecular properties of oligodendrocyte lineage cells both during development and under pathologic conditions. In multiple sclerosis, remyelination of grey matter lesions exceeds that in white matter. Here we used cells derived from grey matter versus white matter regions of surgically resected human brain tissue samples, to compare the capacities of human A2B5-positive progenitor cells and mature oligodendrocytes to ensheath synthetic nanofibers, and relate differences to the molecular profiles of these cells. For both cell types, the percentage of ensheathing cells was greater for grey matter versus white matter cells. For both grey matter and white matter samples, the percentage of cells ensheathing nanofibers was greater for A2B5-positive cells versus mature oligodendrocytes. Grey matter A2B5-positive cells were more susceptible than white matter A2B5-positive cells to injury induced by metabolic insults. Bulk RNA sequencing indicated that separation by cell type (A2B5-positive vs mature oligodendrocytes) is more significant than by region but segregation for each cell type by region is apparent. Molecular features of grey matter versus white matter derived A2B5-positive and mature oligodendrocytes were lower expression of mature oligodendrocyte genes and increased expression of early oligodendrocyte lineage genes. Genes and pathways with increased expression in grey matter derived cells with relevance for myelination included those related to responses to external environment, cell-cell communication, cell migration, and cell adhesion. Immune and cell death related genes were up-regulated in grey matter derived cells. We observed a significant number of up-regulated genes shared between the stress/injury and myelination processes, providing a basis for these features. In contrast to oligodendrocyte lineage cells, no functional or molecular heterogeneity was detected in microglia maintained in vitro, likely reflecting the plasticity of these cells ex vivo. The combined functional and molecular data indicate that grey matter human oligodendrocytes have increased intrinsic capacity to myelinate but also increased injury susceptibility, in part reflecting their being at a stage earlier in the oligodendrocyte lineage.

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Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes

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