Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis

Mendanha Falcão, Ana, van Bruggen, David, Marques, Sueli, Meijer, Mandy, Jäkel, Sarah, Agirre, Eneritz, Samudyata, , Floriddia, Elisa M., Vanichkina, Darya P., ffrench-Constant, Charles ORCID: https://orcid.org/0000-0002-5621-3377, Williams, Anna, Guerreiro-Cacais, André Ortlieb and Castelo-Branco, Gonçalo (2018) Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nature Medicine, 24 (12). pp. 1837-1844. ISSN 1078-8956

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Abstract

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs 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.

Item Type: Article
Additional Information: Funding Information: The G.C.-B., A.W. and C.f.-C. research groups have received funding from F. Hoffmann– La Roche, Ltd. for other research projects in this area. Funding Information: We would like to thank A. Nanni, A. Moshref, Tony Jimenez-Beristain and J. Söderlund for laboratory management and support. We thank Eukaryotic Single Cell Genomics Facility, WABI Long Term Bioinformatic Support (Leif Wigge) at SciLifeLab, the FACS facilities at CMB (B. Panagel), Science for Life Laboratory, the National Genomics Infrastructure and Uppmax for providing assistance in massive parallel sequencing and computational infrastructure. We wish to acknowledge A. G. Rothfuchs for advice and reagents, M. Jagodic for advice, M. Bartosovic for assistance, R. Berglund and M. N’diaye for providing the tools to perform the phagocytosis experiments. The bioinformatics computations were performed on resources provided by the Swedish National Infrastructure for Computing at UPPMAX, Uppsala University. Postmortem MS tissue used for IHC was provided via a UK prospective donor scheme with full ethical approval from the UK Multiple Sclerosis Tissue Bank (MREC/02/02/39). D.P.V. would like to acknowledge the University of Sydney HPC service for providing HPC resources that have contributed to the research reported in this paper. This work was supported in part by a University of Sydney HPC Grand Challenge Award. D.P.V. was supported in part by a Boehringer Ingelheim Travel Grant. C.f.-C. is funded by a Wellcome Trust Investigator award. A.W. is funded by UK Multiple Sclerosis Society. S.J. is funded by European Union, Horizon 2020, Marie-Skłodowska Curie Actions (grant no. EC 789492); A.M.F. by the European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS). E.A. is funded by European Union, Horizon 2020, Marie-Skłodowska Curie Actions (grant no. SOLO 794689). Work in G.C.-B.’s research group was supported by Swedish Research Council (grant no. 2015-03558), European Union (Horizon 2020 Research and Innovation Programme/European Research Council Consolidator Grant EPIScOPE, grant agreement 681893), Swedish Brain Foundation (grant no. FO2017-0075), Ming Wai Lau Centre for Reparative Medicine, Petrus och Augusta Hedlunds Foundation (grant nos. M-2014-0041 and M-2016-0428) and Karolinska Institutet.
Uncontrolled Keywords: biochemistry, genetics and molecular biology(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Jul 2022 14:31
Last Modified: 12 Aug 2022 05:37
URI: https://ueaeprints.uea.ac.uk/id/eprint/86231
DOI: 10.1038/s41591-018-0236-y

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