Related Experiment Video
Updated: Jun 12, 2026
Two-photon Imaging of Cellular Dynamics in the Mouse Spinal Cord
Published on: February 22, 2015
Single-Cell Multi-Omics Map of Cell Type-Specific Mechanistic Drivers of Multiple Sclerosis Lesions
Maria L Elkjaer1, Anne Hartebrodt1, Mhaned Oubounyt1
1From the Department of Neurology (M.L.E., A.W., Z.I.), Odense University Hospital; BRIDGE (M.L.E., A.W., M.T., Z.I.), Department of Clinical Research; Department of Molecular Medicine (M.L.E., A.W., L.V., Z.I.), University of Southern Denmark, Odense, Denmark; Biomedical Network Science Lab (A.H.), Department Artificial Intelligence in Biomedical Engineering, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany; Department of Mathematics and Computer Science (A.H., Richard Rottger, J.B.), University of Southern Denmark, Odense, Denmark; Institute for Computational Systems Biology (M.O., J.B.), University of Hamburg, Germany; Department of Brain Sciences (Richard Reynolds), Imperial College, London, United Kingdom; and Clinical Genome Center (M.T.), Research Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Background And Objectives:
In progressive multiple sclerosis (MS), compartmentalized inflammation plays a pivotal role in the complex pathology of tissue damage. The interplay between epigenetic regulation, transcriptional modifications, and location-specific alterations within white matter (WM) lesions at the single-cell level remains underexplored.
Methods:
We examined intracellular and intercellular pathways in the MS brain WM using a novel dataset obtained by integrated single-cell multi-omics techniques from 3 active lesions, 3 chronic active lesions, 3 remyelinating lesions, and 3 control WM of 6 patients with progressive MS and 3 non-neurologic controls. Single-nucleus RNA-seq and ATAC-seq were combined and additionally enriched with newly conducted spatial transcriptomics from 1 chronic active lesion. Functional gene modules were then validated in our previously published bulk tissue transcriptome data obtained from 73 WM lesions of patients with progressive MS and 25 WM of non-neurologic disease controls.
Results:
Our analysis uncovered an MS-specific oligodendrocyte genetic signature influenced by the KLF/SP gene family. This modulation has potential associations with the autocrine iron uptake signaling observed in transcripts of transferrin and its receptor LRP2. In addition, an inflammatory profile emerged within these oligodendrocytes. We observed unique cellular endophenotypes both at the periphery and within the chronic active lesion. These include a distinct metabolic astrocyte phenotype, the importance of FGF signaling among astrocytes and neurons, and a notable enrichment of mitochondrial genes at the lesion edge populated predominantly by astrocytes. Our study also identified B-cell coexpression networks indicating different functional B-cell subsets with differential location and specific tendencies toward certain lesion types.
Discussion:
The use of single-cell multi-omics has offered a detailed perspective into the cellular dynamics and interactions in MS. These nuanced findings might pave the way for deeper insights into lesion pathogenesis in progressive MS.
