Altered human oligodendrocyte heterogeneity in multiple sclerosis
Open accessAbstract
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 demyelination 1, 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 cortex 2, and single-cell analysis of the mouse central nervous system identified further differences 3,4. 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.
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Post-mortem oligodendrocytes had low but detectable APOE expression.
“Post-mortem oligodendrocytes had low but detectable APOE expression, consistent with previous single-cell resolution reports25 (Extended Data Fig. 5k, l).”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [25]
The Methods (Human Donor tissue; page not given) identify the samples as post-mortem tissue, and the paper identifies APOE as an RNA marker of an oligodendroglial subcluster. It supports detectable APOE expression in that subcluster, but does not establish that expression was low across post-mortem oligodendrocytes generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThese prioritized genes were differentially expressed in MS brain lesion types relative to control white matter.
“These prioritized genes were differentially expressed in MS brain lesion types relative to control white matter26,27 (Supplementary Note, Supplementary Fig. 6).”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [26]
The Methods section, ‘Differential expression analysis between MS Lesions and Control’ (page unavailable), describes a differential-expression analysis of oligodendrocyte-lineage cells. The passage comparing lesion types with control white matter (page unavailable) reports expression differences for several named genes. Our copy does not establish that those genes are the citing document’s ‘prioritized genes,’ so it supports the general finding but not that specific identification. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCell expression of ZNF638 was proportionally enriched in control brain tissue and chronic inactive MS lesions compared to other MS lesions.
“Moreover, cell expression of ZNF638 was proportionally enriched in control brain tissue and chronic inactive MS lesions compared to other MS lesions26.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [26]
The passage discussing lesion markers reports that the proportion of cells expressing several genes was enriched in control white matter and chronic inactive lesions, but not other lesions. It does not name ZNF638 among those genes, and a search for ZNF638 found no supporting passage in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn single-nucleus RNA sequencing from brain white matter areas in MS patients and controls, ZNF638 was preferentially expressed in an oligodendrocyte cluster with a predicted actively myelinating phenotype.
“In single-nucleus RNA sequencing from brain white matter areas in MS patients and controls, ZNF638 was preferentially expressed in an oligodendrocyte cluster with a predicted actively myelinating phenotype26.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [26]
The paper reports single-nucleus RNA sequencing of white matter from controls and people with MS (Abstract; page unavailable). It also describes Oligo3 and Oligo4 as clusters predicted by gene-ontology analysis to be actively myelinating (Abstract; page unavailable). Our copy does not identify ZNF638 as preferentially expressed in either cluster, so the gene-specific finding is not supported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPIGC is expressed in neuronal and glial cells including oligodendrocyte lineage cells in brain white matter tissue.
“Single nuclear RNA expression from 4 progressive MS patients and 5 non-neurological controls26 confirms PIGC expression in neuronal and glial cells including oligodendrocyte lineage cells.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [26]
The paper reports single-nucleus RNA sequencing of white matter from four people with progressive MS and five non-neurological controls (Abstract; page unavailable). It identifies neuronal and glial cell clusters, including oligodendrocyte-lineage cells, but our copy does not report PIGC expression in those cells (searched: “PIGC” and a cell-type expression paraphrase). (LLM, conf=0.84)
Experimental — accuracy not yet measured
MS lesions, particularly the rims of chronic active lesions, contain stressed OLs, reactive astrocytes, and activated phagocytosing microglia/macrophages.
“MS lesions, particularly the rims of chronic active lesions, contain stressed OLs, reactive astrocytes, and activated phagocytosing microglia/macrophages11,12,15.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [11]
The paper’s main text (indexed under Abstract; page unavailable) reports altered oligodendrocyte populations in MS lesions and identifies macrophages and other immune cells in MS tissue. It does not establish that the oligodendrocytes are stressed, that astrocytes are reactive, or that microglia/macrophages are activated and phagocytosing, particularly at chronic-active lesion rims. (LLM, conf=0.82)
Experimental — accuracy not yet measuredA subset of oligodendrocytes, termed immune oligodendrocytes, express PLCG2 mRNA.
“there is some evidence that a subset of oligodendrocytes, termed immune oligodendrocytes, express PLCG2 mRNA (36–38)”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [38]
The passage on oligodendrocyte sub-clusters (section labeled Abstract; page unavailable) identifies immune oligodendroglia (imOLG) and names APOE and CD74 as enriched RNA markers. A later passage in the same section describes their immunological phenotype, but neither passage reports PLCG2 mRNA expression; a search for PLCG2 found no matching passage in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn mouse and human nervous tissue, expression levels of amyloidogenic pathway genes (APP, BACE1, PSEN1 and PSEN2) are similar between neurons and oligodendrocytes.
“transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs).”
From Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice (2024) · cites this paper as [13]
The paper’s Abstract (page not provided) describes oligodendrocyte subclusters and their similarities across human and mouse tissue, but does not compare amyloidogenic-gene expression in oligodendrocytes and neurons. Searches for APP, BACE1, PSEN1, PSEN2, and amyloid precursor protein found no passage addressing the claimed equal abundance. (LLM, conf=0.72)
Experimental — accuracy not yet measuredB2M has been shown to be upregulated in other MS datasets.
“Interestingly, B2M was not significantly upregulated by MOLs in any MS lesion type, however it has been shown to be upregulated in other MS datasets11–13.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [11]
The Extended Data passages describe expression changes for genes including CDH20 and WWOX, but do not report B2M upregulation. Searches for B2M, beta-2 microglobulin, and increased B2M expression in MS returned no passage addressing the claim. (LLM, conf=0.74)
Experimental — accuracy not yet measuredThe overall decreases in myelin lipids in Plcg2 KO mice may be due to cell autonomous effects of PLCG2 loss.
“suggesting that perhaps the overall decreases in myelin lipids in Plcg2 KO mice may be due to cell autonomous effects of PLCG2 loss.”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [38]
The cited paper discusses oligodendrocyte populations and myelin-gene expression in human multiple sclerosis tissue (Abstract; no page supplied). Searches for PLCG2, Plcg2 knockout mice, myelin lipids, and cell-autonomous effects found no passage addressing the proposed explanation for lipid decreases. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe oligodendrocyte signatures observed here differ from those previously linked to multiple sclerosis and senescence.
“These oligodendrocyte signatures are distinct from those recently associated with multiple sclerosis21 and senescence43.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [21]
The study's sample sizes were similar to or greater than those in previous COVID-19 or brain snRNA-seq studies.
“Our sample sizes were similar to or greater than those reported in previous COVID-19 or brain single-nucleus RNA-sequencing (snRNA-seq) studies24-26.”
From Dysregulation of brain and choroid plexus cell types in severe COVID-19 (2021) · cites this paper as [26]
The expression pattern of the AD-up-regulated oligodendrocyte subpopulations o1 and o2 resembles that of remyelinating oligodendrocytes in patients with multiple sclerosis.
“Notably, the transcriptome profiles of the AD-up-regulated oligodendrocyte subpopulations o1 and o2 were characterized by enriched expression of HSPA1A (a heat shock protein), NEAT1 (a nuclear noncoding RNA), and PDE1A (which encodes phosphodiesterase 1A) (SI Appendix, Fig. S5 I and J); this expression pattern resembles that of remyelinating oligodendrocytes in patients with multiple sclerosis (22”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [22]
Nuclei with ≤200 genes, ≥20,000 unique molecular identifiers, or ≥20% mitochondrial genes were filtered out to exclude potential dead cells and cell debris.
“To exclude potential dead cells and cell debris from the dataset, we filtered out nuclei with ≤200 genes, ≥20,000 unique molecular identifiers, or ≥20% mitochondrial genes as described in several previous snRNA-seq studies (12, 13, 22, 53).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [22]
Comparison with Jäkel et al. confirmed the expression patterns of cell-type markers in the different cell types in our study.
“To further confirm the cell-type specificity of these markers, we compared our data with those of Jäkel et al. (22), which confirmed the expression patterns of these markers in the different cell types in our study.”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [22]
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Self-citationPremyelinating Oligodendrocytes: Mechanisms Underlying Cell Survival and Integration
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BackgroundMethodResultRedefining Microglial Identity in Health and Disease at Single-Cell Resolution
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“6a – c and Supplementary Data 4) 26 .”
InfluentialMulti-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain
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- Authors
- Jäkel, S., Agirre, E., Mendanha Falcão, A., van Bruggen, D., Lee, K. W., Knuesel, I., Malhotra, D., ffrench-Constant, C., Williams, A., & Castelo-Branco, G.
- Affiliations
- MRC Centre for Regenerative Medicine (GB)
- Karolinska Institutet (SE)
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Williams, Anna
- Venue
- Nature
- Published
- 2019-01-23
- Volume
- 566
- Issue
- 7745
- Pages
- 543-547
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6544546
- OpenAlex
- W2911725378
- Cited by
- 854
- References
- 38
- Citations by year
- 2026: 110 · 2025: 125 · 2024: 116 · 2023: 118 · 2022: 125 · 2021: 113 · 2020: 93 · 2019: 52 · 2012: 1
- FWCI
- 70.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust (104783/Z/14/Z)
- Multiple Sclerosis Society
- European Commission (681893, HORIZON2020, 789492, 794689)
- Cancerfonden
- Kommunfullmäktige, Stockholms Stad
- Vetenskapsrådet (2015-03558)
- Uppsala Universitet
- Science for Life Laboratory
- Medical Research Council (MR/P016022/1, MR/L016400/1, MR/K026666/1)
- Uppsala Multidisciplinary Center for Advanced Computational Science
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- multiple sclerosis, oligodendroglia, demyelination, white matter, single-nucleus RNA sequencing, oligodendrocyte markers, normal-appearing white matter, disease progression, neurodegeneration
- MeSH terms
- Remyelination, Adult, Aged, Aged, 80 and over, Animals, Autopsy, Brain, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Multiple Sclerosis, Myelin Sheath, Oligodendroglia, Transcription, Genetic, Biomarkers, Case-Control Studies, Sequence Analysis, RNA, Disease Progression, Gene Expression Profiling, Mice, White Matter
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