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Altered oligodendrocyte heterogeneity in Multiple sclerosis.

ABSTRACT: Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes of disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. There was a lack of OL precursor cells (OPCs) and OLs in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118257 | GEO | 2019/01/23

REPOSITORIES: GEO

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Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

Project description:This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

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*Possible corruption in count data files-update in progress* Disease-specific oligodendrocyte lineage cells express immunoprotective and adaptive immunity genes in multiple sclerosis

Project description:Single-cell RNA-seq of a mouse model of MS uncovers new oligodendrocyte populations, putative disease markers and suggests new mechanisms underlying the pathogenesis of disease. In Multiple Sclerosis (MS), oligodendrocytes (OLs) are damaged during an immune system attack targeting myelin. It remains unclear how different OL lineage cells respond to inflammatory autoimmune demyelination in MS. We performed single-cell transcriptomics analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics certain aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE, including populations expressing genes involved in antigen processing and presentation via major histocompatibility complex (MHC) Class I and II, but also in immunoprotection. We further uncovered several genes specifically alternatively spliced in OL lineage cells in EAE, including Mbp, Mobp and Pdgfa. Strikingly, we identified a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells in the context of this disease, to be expressed in the OL lineage cells. Finally, we found that disease-specific oligodendroglia are present in human MS brains. Our results suggest that OL and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.

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