Altered human oligodendrocyte heterogeneity in multiple sclerosis

Jäkel, Sarah, Agirre, Eneritz, Mendanha Falcão, Ana, van Bruggen, David, Lee, Ka Wai, Knuesel, Irene, Malhotra, Dheeraj, ffrench-Constant, Charles ORCID:, Williams, Anna and Castelo-Branco, Gonçalo (2019) Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature, 566 (7745). pp. 543-547. ISSN 0028-0836

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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.

Item Type: Article
Additional Information: Funding Information: Acknowledgements We thank the MS Society UK Tissue Bank and the MRC Sudden Death and MS brain banks for post-mortem brain tissue, Advanced Cell Diagnostics for their help with BaseScope, T. Jimenez-Beristain, A. Nanni and A. Moshref for support, Eukaryotic Single Cell Genomics Facility (ESCGF) at Science for Life Laboratory, L. Wigge (Wallenberg Advanced Bioinformatics Infrastructure (WABI) Long Term Bioinformatic Support at SciLifeLab), the National Genomics Infrastructure, and M. Prasad and F. Koechl at F. Hoffmann-La Roche for providing assistance with snRNA-seq, and B. Vernay, E. O’Duibhir and M. Vermeren (CRM) for imaging support. The bioinformatics computations were performed at Swedish National Infrastructure for Computing (SNIC) at UPPMAX, Uppsala University. Funding: S.J.: European Union, Horizon 2020, Marie-Skłodowska Curie Actions EC no. 789492; C.ff.-C.: Wellcome Trust Investigator award; A.W.: UK Multiple Sclerosis Society, F. Hoffmann-La Roche; E.A.: European Union, Horizon 2020, Marie-Skłodowska Curie Actions, grant SOLO no. 794689; A.M.F.: European Committee for Treatment and Research of Multiple Sclerosis; G.C.-B.: European Union Horizon 2020/European Research Council Consolidator Grant EPIScOPE no. 681893, Swedish Research Council (no. 2015-03558), Swedish Brain Foundation (no. FO2017-0075), Swedish Cancer Society (Cancerfonden, CAN2016/555), Stockholm City Council (grant 20170397), Ming Wai Lau Centre for Reparative Medicine, F. Hoffmann-La Roche.
Uncontrolled Keywords: general,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Jul 2022 14:30
Last Modified: 22 Oct 2022 18:36
DOI: 10.1038/s41586-019-0903-2

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