Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA190060 | ENA |
REPOSITORIES: ENA
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Project description:Failure of remyelination in multiple sclerosis (MS) is associated with inhibition of oligodendrocyte precursor (OPC) differentiation, but the cellular and molecular mechanisms involved remain poorly understood. We now report inflammatory demyelination in MS is associated with localized expression of fibroblast growth factor 9 (FGF9) by oligodendrocytes and to a lesser extent astrocytes, and demonstrate FGF9 inhibits myelination and remyelination in vitro. This inhibitory activity is reversible and due to an off target FGF9-dependent effect on astrocytes that disrupts in the growth factor milieu required to support myelination. We identify multiple downstream events induced by FGF9 associated with this effect including increased expression of leukaemia inhibitory growth factor (LIF) and FGF2, both of which are shown to inhibit myelination if present in excess. These studies identify FGF9-dependent signal transduction in astrocytes as a novel target for therapeutic strategies designed to enhance remyelination by endogenous OPC in MS. Gene expression profiles of rat myelinating cultures grown in the presence or absence of FGF9 (100 ng/ml) for 24h and 10 days were generated using Affymetrix GeneChip® Rat Gene 1.0 ST Arrays. Each time point (T1: 24 hrs, and T2: 10 days) has Control (CTR) and Treatment (FGF) groups, with two replicates in each group. In total, 8 arrays were generated from the four groups (CTR-T1, CTR-T2, FGF-T1 and FGF-T2).
2016-02-17 | E-GEOD-44562 | biostudies-arrayexpress
Project description:Failure of remyelination in multiple sclerosis (MS) is associated with inhibition of oligodendrocyte precursor (OPC) differentiation, but the cellular and molecular mechanisms involved remain poorly understood. We now report inflammatory demyelination in MS is associated with localized expression of fibroblast growth factor 9 (FGF9) by oligodendrocytes and to a lesser extent astrocytes, and demonstrate FGF9 inhibits myelination and remyelination in vitro. This inhibitory activity is reversible and due to an off target FGF9-dependent effect on astrocytes that disrupts in the growth factor milieu required to support myelination. We identify multiple downstream events induced by FGF9 associated with this effect including increased expression of leukaemia inhibitory growth factor (LIF) and FGF2, both of which are shown to inhibit myelination if present in excess. These studies identify FGF9-dependent signal transduction in astrocytes as a novel target for therapeutic strategies designed to enhance remyelination by endogenous OPC in MS.
2016-02-17 | GSE44562 | GEO
Project description:Multiple sclerosis (MS) is an immune-based demyelinating disease. Currently available therapeutics target inflammation but have little impact on promoting remyelination. Furthermore, MS diagnosis is sometimes challenging. Using a demyelination model mice, we previously found that protein tyrosine phosphatase receptor type zeta (PTPRZ) receives abnormal glycosylation, a branched O-mannosyl (O-Man) glycan and that branched O-Man glycosylated PTPRZ specifically occurs in reactive astrocytes of demyelinated lesions. Furthermore, by genetically deleting the branching enzyme, GnT-IX (also known as GnT-Vb), astrogliosis was attenuated and remyelination enhanced. To characterize the PTPRZ expressing astrocytes, microarray analysis was performed using astrocytes from mice after short and long term-cuprizone administration.
2023-07-17 | GSE134372 | GEO
Project description:Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.
| PRJNA985630 | ENA
Project description:Cellular Senescence in Progenitor Cells Contributes to Diminished Remyelination Potential in Progressive Multiple Sclerosis
| PRJNA524718 | ENA
Project description:Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors
| PRJNA259718 | ENA
Project description:Multiple oxygen tension environments reveal diverse patterns of transcriptional regulation in primary astrocytes
| PRJNA138621 | 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:MOCCI, discovered in a screen for mitochondrial peptides that modify inflammatory outcomes, has emerged as a significant regulator of neuroinflammation. Here, we show that MOCCI is upregulated in microglia and astrocytes in both the mouse and human brain upon neuroinflammation, and is required for orchestrating proper, complete, and beneficial activation of microglia and astrocytes. Induction of MOCCI triggers the transition of glial into a neuroprotective state and promotes the resolution of inflammation. In vitro, MOCCI deficiency leads to reduced migration, phagocytosis and cytokine secretion in glia. In the cuprizone mouse model of Multiple Sclerosis, MOCCI plays a role in both demyelination and remyelination: MOCCI deficiency protects against cuprizone-induced oligodendrocyte death and prevents remyelination by inhibiting the clearance of cellular debris.
2025-12-31 | GSE305874 | GEO
Project description:In a previous study performed in our laboratory, the level of FGF1 RNA was found to be increased in remyelinated multiple sclerosis lesions compared to control brain (unpublished observation). Astrocytes play a key role in multiple sclerosis lesion formation. To shed light on potential FGF1-mediated functions in multiple sclerosis, the impact of FGF1 on astrocytes was investigated.
2015-04-10 | E-MTAB-2485 | biostudies-arrayexpress