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BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis

ABSTRACT: BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis

PROVIDER: PRJNA701573 | ENA |

REPOSITORIES: ENA

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BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis

Project description:Extrinsic inhibitors at sites of blood-brain barrier (BBB) disruption and neurovascular damage contribute to remyelination failure in neurological diseases. However, therapies to overcome extrinsic inhibition of remyelination are not widely available and the dynamics of glial progenitor niche remodeling at site of neurovascular dysfunction are largely unknown. By integrating in vivo two-photon (2P) imaging co-registered with electron microscopy and transcriptomics in chronic neuroinflammatory lesions, we found repressed anticoagulation pathways in oligodendrocyte precursor cells (OPCs) that clustered perivascularly at sites of limited remyelination with deposition of fibrinogen, a blood coagulation factor abundantly deposited in multiple sclerosis lesions. By developing the OPC-X-screen to identify compounds that promote remyelination in the presence of extrinsic inhibitors, we showed that known promyelinating drugs did not rescue extrinsic inhibition of remyelination by fibrinogen. In contrast, bone morphogenetic protein (BMP) receptor blockade rescued the inhibitory fibrinogen effects and restored a promyelinating progenitor niche by promoting myelinating oligodendrocytes, while suppressing astrocyte cell fate with potent therapeutic effects in chronic models of multiple sclerosis. Thus, abortive OPC differentiation by fibrinogen is refractory to known promyelinating compounds, suggesting that blockade of the BMP signaling pathway may enhance remyelinating efficacy by overcoming extrinsic inhibition in neuroinflammatory lesions with vascular damage.

2021-08-24 | GSE166675 | GEO

BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis.

Project description: Not available

| S-EPMC8418337 | biostudies-literature

CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents

Project description:In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet improvable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of ‘improved’ OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edited human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplanted them into rodent models of chronic lesions. Edited hOPCs displayed enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. This study demonstrates that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.

2023-08-23 | GSE241451 | GEO

Extrinsic inflammatory, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation block in multiple sclerosis

Project description:Multiple sclerosis (MS) is the most frequent demyelinating disease and despite significant advances in the immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair process, represents a promising new treatment approach. However, spontaneous remyelination frequently fails in MS lesions due to an impaired differentiation of progenitor cells into mature, myelinating oligodendrocytes. Intrinsic oligodendroglial and extrinsic inflammatory factors may contribute to this differentiation block. Therefore, we compared induced pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) from MS patients and healthy controls as well as their response to extrinsic factors. While functional capabilities or proteome compostion of both cell types were virtually indistinguishable, we discovered that Interferon-gamma (IFNÎ³) producing immune cells significantly impaired oligodendroglial differentiation and observed no differences in the functional capabilities or the proteome. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors, but rather caused by the inflammatory environment present in MS lesions. These findings may contribute to the development of remyelination promoting strategies in MS.

2020-09-04 | PXD016043 | Pride

Retinoid X receptor gamma signaling accelerates CNS remyelination

Project description:The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal demyelination in the rat CNS. White matter tracts in the rat caudal cerebellar peduncles were focally demyelinated using 0.1% ethidium bromide, the lesions were isolated using laser capture microdissection at 5, 14 and 28 days postlesion, followed by RNA extraction and Illumina beadarray analysis of differentially expressed transcripts. We found transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination, and that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy. 9 Samples analysed, 3 different time points each with 3 biological replicates.

2010-10-22 | E-GEOD-24821 | biostudies-arrayexpress

Fibrinogen activates BMP signaling in oligodendrocyte progenitor cells (OPCs) and inhibits remyelination after vascular damage [Rat_OPC_48h_Fibrinogen]

Project description:Determination of the mechanism by which fibrinogen, a central blood coagulation protein, regulates OPC functions and remyelination in the CNS. We used microarrays to determine the genes involved in OPC responses to fibrinogen, which is deposited in the CNS after blood-brain barrier disruption.

2017-11-02 | GSE104449 | GEO

Fibrinogen activates BMP signaling in oligodendrocyte progenitor cells (OPCs) and inhibits remyelination after vascular damage [Rat_OPC_12h_Fibrinogen]

2017-11-02 | GSE104448 | GEO

TRAP-seq of mouse astrocytes involved in central nervous system remyelination

Project description:Remyelination failure contributes to axonal dysfunction in neurodegenerative disorders. But whether astrocytes, the most abundant glial cell type in demyelinated lesions, support or impede remyelination is controversial. Following focal demyelinated lesions of the mouse corpus callosum induced with the myelin toxin lysolecithin, we used TRAP (translational ribosome affinity purification) sequencing to isolate and sequence ribosome-associated mRNAs which are being actively translated in astrocytes, and studied how the responses and molecular mechanisms in astrocytes are linked to remyelination.

2023-05-17 | E-MTAB-9270 | biostudies-arrayexpress

Fingolimod and remyelination - Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model

Project description:Remyelinating substances could be an essential supplement to immunomodulatory medications, optimizing the treatment of multiple sclerosis (MS) patients. Fingolimod is a sphingosine-1-phosphate receptor (S1PR) modulator and crosses the blood-brain barrier. Central nervous system (CNS) cells express S1PRs, and Fingolimod could theoretically improve CNS remyelination and be neuroprotective per se, but data are inconsistent. We used the cuprizone model for investigating the effect of fingolimod on remyelination and axonal damage by Immunohistochemistry and quantitative mass spectrometry. After three weeks of remyelination, fingolimod-treated mice had more mature oligodendrocytes in the secondary motor cortex than the placebo group. However, fingolimod did not at any time point affect remyelination or axonal damage. We conclude that fingolimod does not promote remyelination or protect against axonal injury or loss after cuprizone exposure.

2019-11-20 | PXD012676 | Pride

Sequencing of microglia during focal remyelination of the corpus callosum

Project description:The goal of the study was to determine the gene expression of microglia prior to the onset of remyelination (3 days post lysolecithin injection) and pro-regenerative microglia at the onset of remyelination (10 days post remyelination).

2019-05-24 | GSE118450 | GEO

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