Summary: New research reveals distinct populations of brain cells linked to multiple sclerosis (MS). Scientists found multiple types of oligodendrocytes and a markedly different balance of these cells in people with progressive MS compared with healthy brains. These discoveries offer fresh directions for therapies aimed at restoring myelin and slowing disease progression.
Source: University of Edinburgh.
Study reveals new details about brain cell types involved in multiple sclerosis, opening paths for more targeted treatments.
Researchers focused on cells that support and repair the insulating layer around nerve fibres — a layer called myelin, which is damaged in MS.
The team identified several distinct types of oligodendrocytes, the cells responsible for forming and repairing myelin. Their analysis shows that people with progressive MS have a different ratio of these oligodendrocyte types compared with people without neurological disease.
These differences indicate that oligodendrocytes may function differently in MS, potentially explaining why myelin repair is less effective in affected brains. Understanding these differences could help researchers design treatments that more precisely target the cells that promote repair.
Scientists at the University of Edinburgh and the Karolinska Institute examined post-mortem brain tissue from nine individuals: five without neurological disease and four with progressive MS, the most advanced clinical form of the condition. Working alongside researchers from Hoffmann‑La Roche, the group used single-nucleus RNA sequencing (snRNA‑seq), a technique that captures a snapshot of all genes active in an individual cell nucleus.
snRNA‑seq allows researchers to profile thousands of cells and to classify distinct cellular states based on gene-expression patterns. Applying this approach to white matter regions of the human brain, the investigators mapped the diversity of oligodendrocytes and other glial cells in both control and MS tissue.
The results confirmed that human white matter contains multiple oligodendrocyte subtypes. Crucially, the relative abundance of these subtypes was altered in MS samples: some oligodendrocyte subpopulations were under‑represented in MS tissue, while others were more common. These shifts were not confined to obvious lesion areas but were also present in normal‑appearing white matter, suggesting that MS causes widespread changes in oligodendrocyte composition across the brain.
Oligodendrocytes not only form myelin but also provide metabolic support to axons. When myelin is lost in MS, nerve conduction slows and axons become vulnerable to degeneration. Many experimental treatments aim to stimulate oligodendrocytes or their precursors to enhance remyelination, so a clearer picture of oligodendrocyte diversity in humans is directly relevant for therapy development.
Previous single‑cell studies in mice had already suggested oligodendrocyte heterogeneity, with different subtypes performing distinct roles. This new human study is the first to map multiple oligodendrocyte states in the human brain and to show that their distribution differs between healthy individuals and people with MS. The researchers also observed that the pattern of oligodendrocyte types in humans differs from that in mice, implying important species differences that should be considered when translating animal findings to human disease.
Multiple sclerosis is a chronic neurological disorder that can cause imbalance, fatigue and progressive disability. Around 2.5 million people live with MS worldwide. Effective treatments exist for some forms of MS, but there are currently no approved therapies that reliably halt or reverse progression in the progressive phase of the disease.
The study appears in the journal Nature and was supported by the UK MS Society, the European Union, the European Research Council, the European Committee for Treatment and Research in Multiple Sclerosis, the Wellcome Trust and other funders.
Professor Charles ffrench‑Constant, of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh, said: “We found that oligodendrocytes are a diverse population of cells and that different types are likely to have different functions in the brain.”
Professor Anna Williams, also at the MRC Centre for Regenerative Medicine, added: “Understanding which types of oligodendrocytes are most effective in repairing myelin will be crucial for maximising the chances of developing much‑needed treatments for MS.”
Associate Professor Gonçalo Castelo‑Branco of the Karolinska Institute commented: “Our findings highlight the power of single‑cell genomics to study human disease. Applying this technology to larger sample collections should deepen our understanding of how MS develops and why it progresses in some people.”
Dr Susan Kohlhaas, Director of Research at the MS Society, said: “More than 100,000 people in the UK have MS and many still lack effective options. People with progressive MS urgently need treatments that repair myelin and stop disability from worsening. Research like this brings us closer to that goal.”
Source: Jen Middleton — University of Edinburgh
Publisher: NeuroscienceNews.com (organized summary)
Image source: NeuroscienceNews.com image in the public domain.
Original research: Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature. Authors include Sarah Jäkel, Eneritz Agirre, Ana Mendanha Falcão, David van Bruggen, Ka Wai Lee, Irene Knuesel, Dheeraj Malhotra, Charles ffrench‑Constant, Anna Williams and Gonçalo Castelo‑Branco. DOI: 10.1038/s41586-019-0903-2.
Altered human oligodendrocyte heterogeneity in multiple sclerosis
Oligodendrocyte pathology is increasingly recognised as a contributor to neurodegenerative processes because oligodendrocytes both form myelin and support axonal metabolism. In MS, demyelination of the central nervous system contributes to neurodegeneration, but disease severity varies greatly between patients and does not always correlate directly with the amount of demyelination. One possible source of this variability is oligodendrocyte heterogeneity. Prior mouse studies revealed regional and functional differences among oligodendrocytes, but the extent of such diversity in humans and its role in MS was unclear. Using single‑nucleus RNA sequencing of white matter from control and MS post‑mortem brains, the authors identified multiple oligodendroglial subclusters in human tissue, some analogous to those described in mice and others newly defined. Several mature oligodendrocyte subclusters were depleted in MS samples while others increased, suggesting shifts in oligodendrocyte states in disease. Because these changes were also present in normal‑appearing white matter, MS appears to cause more diffuse alterations than focal demyelinating lesions alone would suggest. These observations of altered oligodendroglial heterogeneity may be important for understanding disease progression and for developing targeted regenerative therapies.