Altered oligodendrocyte heterogeneity in Multiple sclerosis.
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ABSTRACT:
PROVIDER: PRJNA484965 | ENA |
REPOSITORIES: ENA
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Project description:Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes of disease 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 multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. There was a lack of OL precursor cells (OPCs) and OLs in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.
2019-01-23 | GSE118257 | GEO
Project description: Not available
| S-SUBS11 | biostudies-other
Project description: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 demyelination1, 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 cortex2, and single-cell analysis of the mouse central nervous system identified further differences3,4. 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.
| S-EPMC6544546 | biostudies-literature
Project description:This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below:
https://www.ebi.ac.uk/ena/browser/view/PRJEB39323
Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease 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 multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.
| EGAS00001003412 | EGA
Project description:Progressive multiple sclerosis
| PRJNA966951 | ENA
Project description:Diverse injury responses of human oligodendrocyte to mediators implicated in multiple sclerosis
| PRJNA1048940 | ENA
Project description:Cell type specificity of intralocus interactions reveals oligodendrocyte intrinsic mechanisms for multiple sclerosis
| PRJNA595883 | ENA
Project description:This study provides an overview of the transcriptional signature of oligodendrocyte progenitor cells (OPCs) exposed to the CSF collected from multiple sclerosis patients with either a relapsing remitting disease course (RRMS) or a confirmed primary progressive diagnosis (PPMS). Using an Affymetrix microarray we were able to detect a set of common and unique genes for each treatment group. Gene ontology analysis revealed a common group of genes involved in protein transport, actin dynamics and response to stress and DNA damage, while the RRMS-specific genes were grouped according to protein complex biogenesis, nuclear transport and RNA processing. The transcriptional signature of progenitors exposed to PPMS was characterized by an up-regulation of the pro-differentiation adhesion molecule Lgals3. We confirmed increased protein levels of its gene product,product; galectin-3 in proliferating OPCs incubated with CSF from PPMS patients and also found a four-fold increase in mRNA transcript levels of galectin-3 in human post-mortem normal-appearing white matter samples of primary progressive MS patients when compared to non-neurological controls. This study will help to better understand the common and specific transcriptional changes induced in the different subtypes of MS and therefore find more specific molecular targets for each disease subtype. Comparison of transcriptional signature by microarray analysis of OPCs treated with RRMS and PPMS CSF.
2015-06-19 | E-GEOD-60881 | biostudies-arrayexpress