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Altered human oligodendrocyte heterogeneity in multiple sclerosis

Nature (2019) | Download Citation

Abstract

Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases as OLs both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system (CNS) thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, suggesting that other factors contribute to this variability. One such factor may be OL heterogeneity. Not all OLs are the same—mouse spinal cord OLs inherently produce longer myelin sheaths than cortical OLs2, and single-cell analysis of mouse CNS identified further differences3,4. However, the extent of human OL heterogeneity and its possible contribution to MS pathology 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 MS patients. We identified sub-clusters of oligodendroglia in Ctr human WM, some similar to mouse, and defined new markers for these cell states. Strikingly, some sub-clusters were under-represented in MS tissue, while others were more prevalent. These differences in mature OL sub-clusters may indicate different functional states of OLs in MS lesions. Since this is similar in normal appearing white matter (NAWM), MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important to understanding disease progression and developing therapeutic approaches.

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Author information

Author notes

  1. These authors contributed equally: Sarah Jäkel, Eneritz Agirre.

  2. These authors jointly supervised the work: Dheeraj Malhotra, Charles ffrench-Constant, Anna Williams, Gonçalo Castelo-Branco.

Affiliations

  1. MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, University of Edinburgh, Edinburgh, UK

    • Sarah Jäkel
    • , Charles ffrench-Constant
    •  & Anna Williams
  2. Laboratory of Molecular Neurobiology, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    • Eneritz Agirre
    • , Ana Mendanha Falcão
    • , David van Bruggen
    • , Ka Wai Lee
    •  & Gonçalo Castelo-Branco
  3. Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland

    • Irene Knuesel
    •  & Dheeraj Malhotra
  4. Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, Stockholm, Sweden

    • Gonçalo Castelo-Branco

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Corresponding authors

Correspondence to Charles ffrench-Constant or Anna Williams or Gonçalo Castelo-Branco.

Supplementary information

  1. Supplementary Figure 1

    Raw image file of MRF Western Blot for Extended Data Fig. 8f. Left lane: protein ladder. Middle and right lane: duplicates of human protein lysates. Dashed box indicates cropped region. Loading control was not used as no quantitative measures were taken.

  2. Reporting Summary

  3. Supplementary Table 1

    A List of human donor tissue, including frozen samples used in snRNA-Seq and paraffin samples used in ISH and IHC validations, with sex, age at death, cause of death, MS type and disease duration, when available. Abbreviations: M=male, F=female, SP=secondary progressive, PP=primary progressive, NA=not available.

  4. Supplementary Table 2

    Sequencing statistics of the 20 samples used for the study, quantification of number of nuclei positive for OL marker combinations (relative to Fig. 1c right) and QC stats of the available published snRNA-seq dataset (relative to Extended Data Fig. 2). n=17799 nuclei derived from 5 Ctr and 4 MS patients.

  5. Supplementary Table 3

    A list of differentially expressed genes for each of the 23 cell type clusters. (Bonferroni corrected Wilcoxon Rank Sum two tailed test, adjusted p-val < 0.05). n= number of individual nuclei, nAstrocytes=1046, nAstrocytes2=196, nCOPs=242, nEndothelial_cells1=452, nEndothelial_cells2=384, nMacrophages=368, nImmune_cells=423, nMicroglia_Macrophages=428, nNeuron1=1507, nNeuron2=1438, nNeuron3=543, nNeuron4=948, nNeuron5=595, nImOLGs=207, nOligo2=1839, nOligo4=1579, nOligo6=1484, nOligo5=1167, nOligo1=1129, nOligo3=775, nOPCs=352, nPericytes=585 and nVasc_smooth_muscle=112.

  6. Supplementary Table 4

    A list of differentially expressed genes for the 9 OL clusters, when considering only the OL lineage, and selection of OL markers. n= number of individual nuclei, nOPC=352, nCOP=242, nImOLG=207, nOligo1=1129, nOligo2=1839, nOligo3=775, nOligo4=1579, nOligo5=1167, nOligo6=1484. Bonferroni corrected Wilcoxon Rank Sum two tailed test, adjusted p-val < 0.05.

  7. Supplementary Table 5

    Comparison of human Ctr and MS OL snRNA-seq and mouse EAE oligodendroglia scRNA-seq datasets shows similarities and differences in OL heterogeneity (related to Extended Figure 5). Selected top hits with mean AUROC values >= 0.5 for unsupervised classification of cell type pairs between human (current dataset) and mouse OLs (Falcao, van Bruggen et al. 2018).

  8. Supplementary Table 6

    A list of differentially expressed genes in Ctrl Vs. MS nuclei in OL clusters (related to Fig. 3e and Extended Figure 8h). (Bonferroni corrected Wilcoxon Rank Sum two tailed test, adjusted p-val < 0.05).

  9. Supplementary Table 7

    A list of differentially expressed genes between different types of lesions within OL clusters. (Bonferroni corrected Wilcoxon Rank Sum two tailed test, adjusted p-val < 0.05). (nOPC=79, nCOP=89, nImOLG=126, nOligo1=177, nOligo2=1451, nOligo3=693, nOligo4=855, nOligo5=774, nOligo6= 493).

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DOI

https://doi.org/10.1038/s41586-019-0903-2

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