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Single-cell RNA-sequencing identifies putative multiple sclerosis-associated microglial subtypes
ECTRIMS Online Library. Menon V. Oct 12, 2018; 232053
Vilas Menon
Vilas Menon
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Abstract: 300

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Neurobiology

Introduction: Our understanding of human microglia is advancing rapidly as modern transcriptome-wide assessments - along with proteomic and epigenomic studies of bulk microglia - have provided new insights into the role of this cell type in brain development, central nervous system tissue homeostasis and neurodegenerative diseases, including Multiple Sclerosis (MS). However, our understanding of the diversity of cell states that microglia can adopt in the human brain remains limited; microglia are highly plastic and have multiple different roles, making the extent of intra-individual heterogeneity a central question for potential therapies targeting this cell type.
Objectives: Our goal was to characterize the diversity of human microglia isolated from human cortical samples, and to identify putative transcriptomic subtypes.
Aims: 1) To reliably isolate and profile human cortical microglia using single-cell RNA-sequencing, 2) To cluster microglia into cell types based on their transcriptomic profiles, 3) To examine genes up- and down-regulated in microglial types to identify putative populations associated with MS.
Methods: We extracted and isolated CD45+/CD11b+/7AAD- cells from from human cortical samples, thus strongly enriching for microglia, and profiled these cells using the 10x Genomics Chromium platform. We obtained 15,910 cells isolated from the cerebral cortices of 7 aged as well as 8 young and middle-aged adults, with each cell having at least 1000 Unique Molecular Identifiers (transcripts). We clustered cells by transcriptomic profile using an iterative PCA-Louvain approach, and characterized sets of genes up- and down-regulated in each cluster.
Results: We identified 16 putative microglial (IBA1+) clusters, including two that were highly enriched for genes associated with MS and demyelination. These clusters have a set of gene markers (CXCR4/IFI6/NACA2/LAMTOR2 and FCGBP/LIPA) that allow them to be potentially isolated or marked for further functional analysis.
Conclusions: This study provides an overview of microglial heterogeneity, including the identification of two putative microglial subtypes with possible association to MS. Although the number of donors is small, and the association to MS is through gene-set enrichment analyses as opposed to a direct association, this initial relationship between a subset of microglia and MS suggests one potential cell type-specific avenue for immune-mediated dysregulation in MS.
Disclosure: This study was funded by NIH grant RF1 AG057473 Vilas Menon: Nothing to disclose
Marta Olah: Nothing to disclose
Elizabeth Bradshaw: Nothing to disclose
Wassim Elyaman: Nothing to disclose
Mariko Taga: Nothing to disclose
Philip De Jager: Member of an advisory board: Celgene, Roche, Sanofi/GenzymePhilip De Jager: Sponsored research: Eisai, Roche, Biogen, Lundbeck
Philip De Jager: Speaker honorarium: GlaxoSmithKline

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