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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:Accumulating myelin damage and impaired remyelination are central pathological features of leukoencephalopathies, including Multiple Sclerosis and Alexander Disease, where astrocytes play essential roles in maintaining central nervous system homeostasis and mediating astrocyte-oligodendrocyte interactions. Chloride Ion Channel 2 (ClC-2), encoded by CLCN2, is functionally expressed in astrocytes and is likely critical to white matter integrity; however, its precise roles and interactions remain unclear. Clarifying the mechanisms by which astrocytic ClC-2 influences white matter is essential for developing treatments for CLCN2-related leukoencephalopathy (CC2L) and potentially other white matter disorders. In this study, we demonstrate that dysfunctional ClC-2 in astrocytes—derived from both mouse models and human-induced pluripotent stem cells (hiPSCs)—impairs oligodendrocyte lineage cell development in vitro and delays remyelination in vivo. Transcriptomic analyses identified SPP1 as a key inhibitory factor on remyelination, secreted from ClC-2-deficient astrocytes. This inhibition was validated through astrocyte-specific modulation of SPP1 expression, where overexpression exacerbated, and downregulation alleviated, demyelination effects. Furthermore, we discovered that SPP1 upregulation in astrocytes with abnormal ClC-2 negatively impacts remyelination by interacting with CD44 on oligodendrocyte progenitor cells. Finally, we confirmed that increased SPP1 expression and the resulting suppression of oligodendrocyte lineage cell development were also present in hiPSC-derived astrocytes harboring a CLCN2 mutation from a CC2L patient. Collectively, these findings reveal that astrocytic ClC-2 is intricately linked to white matter integrity through SPP1 regulation, positioning it as a potential therapeutic target for CC2L and other leukoencephalopathies.
2026-06-02 | GSE298674 | GEO
Project description:Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.
| PRJNA985630 | ENA
Project description:Knee osteoarthritis (KOA), as a degenerative multifactorial disease, affects the quality of life and mental health of patients, and also brings a huge socioeconomic burden. Treating synovitis have shown promise as anti-inflammatory therapeutics in mitigating OA symptoms and disease progression. Here, by analysing synovial single-cell sequencing (scRNA-seq) data from KOA, we found that synovial fibroblasts (FLS) in OA synovium showed a distinct pro-inflammatory phenotype. We collected synovial tissue from patients with clinical OA as well as from healthy donors, and histological examination was consistent with findings in scRNA-seq. Inspired by recent cross-tissue fibroblast lineage studies, we identified by sequencing that healthy FLS in synovial tissues share transcriptome-level similarities with dermal fibroblasts (DFb). Subsequently, we revealed the local as well as systemic distribution of intra-articular injected DFbs by constructing/extracting two types of rat fibroblasts (luciferase DFbs as well as GFP DFbs). The results demonstrate that DFbs can be locally retained in the synovium for up to three weeks following targeted engrafting on it. And intra-articular injection does not result in DFbs migration to vital organs or the occurrence of histological changes in these organs. A rat model of KOA was constructed by anterior cruciate ligament transection (ACLT) in order to study the therapeutic effect of DFbs on KOA. After injection, the rats showed improvement in painful gait. In addition, histological as well as imaging results showed reduced synovitis and improvement in articular cartilage. Finally we verified the protective effect of DFbs on cytokine-stimulated chondrocytes in a co-culture system.
2026-06-24 | GSE304724 | GEO
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