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Nature. 2019 Feb;566(7745):543-547. doi: 10.1038/s41586-019-0903-2. Epub 2019 Jan 23.

Altered human oligodendrocyte heterogeneity in multiple sclerosis.

Author information

1
MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, University of Edinburgh, Edinburgh, UK.
2
Laboratory of Molecular Neurobiology, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
3
Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland.
4
MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, University of Edinburgh, Edinburgh, UK. cffc@ed.ac.uk.
5
MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, University of Edinburgh, Edinburgh, UK. anna.williams@ed.ac.uk.
6
Laboratory of Molecular Neurobiology, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. goncalo.castelo-branco@ki.se.
7
Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, Stockholm, Sweden. goncalo.castelo-branco@ki.se.

Abstract

Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the same-those from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex2, and single-cell analysis of the mouse central nervous system identified further differences3,4. However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches.

PMID:
30747918
DOI:
10.1038/s41586-019-0903-2
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