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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE166675 | GEO | 2021/08/24

REPOSITORIES: GEO

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

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

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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

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

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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

Primary cilia control Oligodendrocyte Precursor Cell proliferation in white matter injury via Hedgehog-independent CREB signaling.

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2023-09-29 | GSE243997 | GEO

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

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 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).

2016-02-17 | E-GEOD-44562 | biostudies-arrayexpress

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

2016-02-17 | GSE44562 | GEO

PARP1-mediated PARylation activity is essential for oligodendroglial differentiation and CNS myelination

Project description:The function of poly(ADP-ribosyl) polymerase 1 (PARP1) in myelination and remyelination of the central nervous system (CNS) remains enigmatic. Here we report that PARP1 is an intrinsic driver for oligodendroglial development and myelination. Genetic PARP1 depletion impairs the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and impedes CNS myelination. Mechanistically, PARP1-mediated PARylation activity is not only necessary but also sufficient for OPC differentiation. At the molecular level, we identify the RNA-binding protein Myef2 as a PARylated target which controls OPC differentiation through PARylation-modulated de-repression of myelin protein expression. Furthermore, PARP1’s enzymatic activity is necessary for oligodendrocyte and myelin regeneration after demyelination. Together, our findings suggest that PARP1-mediated PARylation activity may be a potential therapeutic target for promoting OPC differentiation and remyelination in neurological disorders characterized by arrested OPC differentiation and remyelination failure such as multiple sclerosis.

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Project description:Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors oligodendrocyte precursor cells (OPCs) have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a strategy for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects, possibly even synergistic effects, on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS.

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