Unknown,Transcriptomics,Genomics,Proteomics

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Fibroblast growth factor 9 inhibits remyelination via an off target effect on astrocytes in multiple sclerosis

ABSTRACT: 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 GeneChipÂ® 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).

ORGANISM(S): Rattus norvegicus

SUBMITTER: Manikhandan Mudaliar

PROVIDER: E-GEOD-44562 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Fibroblast growth factor 9 inhibits remyelination via an off target effect on astrocytes in multiple sclerosis

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