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Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE60881 | GEO | 2015/06/19

SECONDARY ACCESSION(S): PRJNA259718

REPOSITORIES: GEO

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Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors

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

Transcriptional abnormalities in iPSC-derived oligodendrocytes of individuals with primary progressive multiple sclerosis

Project description:Multiple sclerosis (MS) is the most common neurological disorder in young adults and is classically defined as a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although MS affects millions of people worldwide, its underlying cause remains unknown making discovery of effective treatments challenging. Whether intrinsic or extrinsic factors contribute to MS initiation and progression is still unclear. This is especially true for primary progressive MS (PPMS), the rarest form of the disease, in which progressive and irreversible loss of neurological function is often observed in the absence of an overt immune-inflammatory response. To test the hypothesis that intrinsic dysfunction in oligodendrocytes (OLs), the primary targets of damage in MS, may contribute to PPMS etiopathology, we differentiated human induced pluripotent stem cell (hiPSC) lines derived from PPMS and healthy individuals into mature OLs to compare their transcriptional profile. PPMS derived OLs displayed hundreds of differentially expressed genes compared to control OLs, many associated with cell adhesion, apoptosis and inflammation, including the inflammasome component Nlrp2, which was highly upregulated. NLRP2 immunoreactivity in OLs was confirmed in post-mortem PPMS brain tissues, with higher expression than in control tissues. Altogether, our findings suggest that mature OLs in PPMS affected individuals carry intrinsic abnormalities that could contribute, at least in part, to the pathophysiology of this form of the disease.

2022-08-26 | GSE211739 | GEO

Multiple Sclerosis Blood Cell mRNA Transcriptome

2010-04-02 | GSE17048 | GEO

Cellular Senescence in Progenitor Cells Contributes to Diminished Remyelination Potential in Progressive Multiple Sclerosis

Project description:Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from primary progressive multiple sclerosis (PPMS) patient induced pluripotent stem (iPS) cell lines failed to promote oligodendrocyte progenitor cell (OPC) maturation whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS autopsy brain tissues and PPMS patient iPS-derived NPCs. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin which then enhanced PPMS NPC support for oligodendrocyte differentiation. A proteomic analysis of the PPMS NPC secretome identified high mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of oligodendrocyte differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in progressive MS which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

2019-11-12 | PXD013060 | Pride

Multiple Sclerosis Blood Cell mRNA Transcriptome

Project description:We measured mRNA expression for all known genes in whole blood from 144 individuals, 99 with MS (43 PPMS, 36 RRMS and 20 SPMS). Analysis of gene expression and genotype in these individuals has indicated the dominant genetic association with T cell regulation is matched by the dominant pattern of dysregulation of T cell gene expression in MS and its clinical subtypes. Whole blood mRNA expression was compared between different types of MS and age-matched healthy control to identify differentially expressed genes between them. The supplementary file 'GSE17048_non-normalized_data.txt' contains non-normalized data for Samples GSM426595-GSM426738.

2010-04-13 | E-GEOD-17048 | biostudies-arrayexpress

Transcriptome data of B cells from patients with multiple sclerosis and healthy controls

Project description:We analyzed the transcriptome profile of B cells from patients with relapsing-remitting multiple sclerosis (RRMS), patients with primary progressive multiple sclerosis (PPMS) and healthy individuals. High-density Clariom D Arrays for human were used to quantify the transcript levels. This GEO entry provides the processed Clariom D microarray data from the gene-level and exon-level workflows.

2021-12-14 | GSE190847 | GEO

Microarray expression analysis of PRF1 (perforin 1) haplotypes in patients with primary progressive multiple sclerosis

Project description:A genetic study of the PRF1 gene has shown association of several polymorphisms with multiple sclerosis (MS). Haplotype analysis identified risk haplotypes strongly associated with male patients having the primary-progressive form of MS (PPMS). Gene expression microarrays were performed in 10 male PPMS patients carrying the risk (n=6) and protective haplotypes (n=4) in order to identify pathways associated with the risk haplotypes. Pathway analysis revealed overrepresentation of the cell killing gene ontology category among down-regulated genes in patients carrying risk haplotypes compared with patients carrying protective haplotypes.

2010-07-28 | GSE23205 | GEO

Transcription profiling of peripheral blood from patients with primary progressive multiple sclerosis to compare risk and protective PRF1 haplotypes

2010-07-28 | E-GEOD-23205 | biostudies-arrayexpress

CSF B cells in relapsing multiple sclerosis are driven towards an antigen-experienced, inflammatory fate

Project description:Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-?B) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-ß1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

2020-08-31 | GSE133028 | GEO

Human cerebrospinal fluid autoantibody lipid microarray profiling (Fig. 1A)

Project description:Lipids comprise 70% of the myelin sheath, and autoantibodies against lipids may contribute to the demyelination that characterizes multiple sclerosis (MS). We used lipid antigen microarrays and lipid mass spectrometry to identify bona fide lipid targets of the autoimmune response in MS brain and an animal model of MS to explore the role of the identified lipids in autoimmune demyelination. We found that autoantibodies in MS target a phosphate group in phosphatidylserine and oxidized phosphatidylcholine derivatives. Administration of these lipids ameliorated experimental autoimmune encephalomyelitis by suppressing activation and inducing apoptosis of autoreactive T cells, effects mediated by the lipids' saturated fatty-acid side chains. Thus, phospholipids represent a natural anti-inflammatory class of compounds that have potential as novel therapeutics for MS. Fig. 1A. Lipid-array profiling of IgG+IgM antibody reactivity in cerebrospinal fluid (CSF) samples from MS patients (relapsing remitting MS; secondary progressive MS; primary progressive MS), healthy controls, and other neurological disease controls. Lipid hits with the lowest FDR (q=0.048) were clustered according to their reactivity profiles. 48 different lipids were custom-spotted in duplicate using the CAMAG Automatic TLC Sampler (ATS4) robot to spray 200 nl of 10 to 100 pmol of lipids onto PVDF membranes affixed to the surface of microscope slides. The slides were probed with cerebrospinal fluid (CSF) from 59 human patient samples. 60 slides total: 18 relapsing-remitting MS, 14 secondary-progressive MS, 1 primary-progressive MS, 21 other neurological disease, 5 healthy control, 1 secondary Ab alone (not included in this submission). CSF diluted 1/10. HRP-conjugated secondary Ab (goat anti-human IgM/IgG) diluted 1/8000. ECL for 3 minutes.

2012-05-08 | E-GEOD-37664 | biostudies-arrayexpress

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