Ontology highlight
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PROVIDER: PRJEB39323 | ENA |
REPOSITORIES: ENA
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Project description:Altered oligodendrocyte heterogeneity in Multiple sclerosis.
| PRJNA484965 | ENA
Project description:Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients. RNA sequencing of oligodendrocyte progenitor cells treated with vehicle, miconazole or clobetasol for 0, 2, 6, or 12 hours. Cells were plated 1.5 hours prior to addition of drug.
2015-04-13 | E-GEOD-63804 | biostudies-arrayexpress
Project description:Using the Illumina 450K array and a stringent statistical analysis with age and gender correction, we report genome-wide differences in DNA methylation between pathology-free regions derived from human multiple sclerosis–affected and control brains. Differences were subtle, but widespread and reproducible in an independent validation cohort. The transcriptional consequences of differential DNA methylation were further defined by genome-wide RNA-sequencing analysis and validated in two independent cohorts. Genes regulating oligodendrocyte survival, such as BCL2L2 and NDRG1, were hypermethylated and expressed at lower levels in multiple sclerosis–affected brains than in controls, while genes related to proteolytic processing (for example, LGMN, CTSZ) were hypomethylated and expressed at higher levels. These results were not due to differences in cellular composition between multiple sclerosis and controls. Thus, epigenomic changes in genes affecting oligodendrocyte susceptibility to damage are detected in pathology-free areas of multiple sclerosis–affected brains.
2013-11-24 | GSE40360 | GEO
Project description:Diverse injury responses of human oligodendrocyte to mediators implicated in multiple sclerosis
| PRJNA1048940 | ENA
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2023-09-01 | GSE183160 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2023-09-01 | GSE182558 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2023-09-01 | GSE182245 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
2024-11-02 | GSE280851 | GEO
Project description:Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.
2015-04-13 | GSE63804 | GEO
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