6 results on '"Abdelmoumen Kassoussi"'
Search Results
2. The Smoothened agonist SAG Modulates the Male and Female Peripheral Immune Systems Differently in an Immune Model of Central Nervous System Demyelination
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Abdelmoumen Kassoussi, Amina Zahaf, Tom Hutteau-Hamel, Claudia Mattern, Michael Schumacher, Pierre Bobé, and Elisabeth Traiffort
- Subjects
oligodendrocyte ,microglia ,myelination ,Hedgehog signaling ,androgen ,cytokine ,Cytology ,QH573-671 - Abstract
Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females. Here, we developed an intranasal formulation containing the Hedgehog signaling agonist SAG, either alone or in combination with testosterone. We show that SAG promotes myelin regeneration and presumably a pro-regenerative phenotype of microglia, thus mimicking the effects previously observed in males. However, unlike in males, the combined molecules failed to cooperate in the demyelinated females, as shown by the level of functional improvement observed. Consistent with this observation, SAG administered in the absence of testosterone amplified peripheral inflammation by presumably activating NK cells and thus counteracting a testosterone-induced reduction in Th17 cells when the molecules were combined. Altogether, the data uncover a sex-dependent effect of the Hedgehog signaling agonist SAG on the peripheral innate immune system that conditions its ability to cooperate or not with androgens in the context of demyelination.
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- 2024
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3. Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation
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Alice Del Giovane, Mariagiovanna Russo, Linda Tirou, Hélène Faure, Martial Ruat, Sonia Balestri, Carola Sposato, Francesco Basoli, Alberto Rainer, Abdelmoumen Kassoussi, Elisabeth Traiffort, and Antonella Ragnini-Wilson
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remyelinating drugs ,oligodendrocyte ,differentiation ,multiple sclerosis ,hedgehog signaling ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The regeneration of myelin is known to restore axonal conduction velocity after a demyelinating event. Remyelination failure in the central nervous system contributes to the severity and progression of demyelinating diseases such as multiple sclerosis. Remyelination is controlled by many signaling pathways, such as the Sonic hedgehog (Shh) pathway, as shown by the canonical activation of its key effector Smoothened (Smo), which increases the proliferation of oligodendrocyte precursor cells via the upregulation of the transcription factor Gli1. On the other hand, the inhibition of Gli1 was also found to promote the recruitment of a subset of adult neural stem cells and their subsequent differentiation into oligodendrocytes. Since Smo is also able to transduce Shh signals via various non-canonical pathways such as the blockade of Gli1, we addressed the potential of non-canonical Smo signaling to contribute to oligodendroglial cell maturation in myelinating cells using the non-canonical Smo agonist GSA-10, which downregulates Gli1. Using the Oli-neuM cell line, we show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMP-activated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. Moreover, GSA-10 promotes the recruitment and differentiation of oligodendroglial progenitors into the demyelinated corpus callosum in vivo. Altogether, our data indicate that non-canonical signaling involving Smo/AMPK modulation and Gli1 downregulation promotes oligodendroglia maturation until axon engagement. Thus, GSA-10, by activation of this signaling pathway, represents a novel potential remyelinating agent.
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- 2022
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4. Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions
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Elisabeth Traiffort, Abdelmoumen Kassoussi, Amina Zahaf, and Yousra Laouarem
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oligodendrocyte ,myelination ,remyelination ,astrocyte ,microglia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Myelination is an essential process that consists of the ensheathment of axons by myelin. In the central nervous system (CNS), myelin is synthesized by oligodendrocytes. The proliferation, migration, and differentiation of oligodendrocyte precursor cells constitute a prerequisite before mature oligodendrocytes extend their processes around the axons and progressively generate a multilamellar lipidic sheath. Although myelination is predominately driven by oligodendrocytes, the other glial cells including astrocytes and microglia, also contribute to this process. The present review is an update of the most recent emerging mechanisms involving astrocyte and microglia in myelin production. The contribution of these cells will be first described during developmental myelination that occurs in the early postnatal period and is critical for the proper development of cognition and behavior. Then, we will report the novel findings regarding the beneficial or deleterious effects of astroglia and microglia, which respectively promote or impair the endogenous capacity of oligodendrocyte progenitor cells (OPCs) to induce spontaneous remyelination after myelin loss. Acute delineation of astrocyte and microglia activities and cross-talk should uncover the way towards novel therapeutic perspectives aimed at recovering proper myelination during development or at breaking down the barriers impeding the regeneration of the damaged myelin that occurs in CNS demyelinating diseases.
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- 2020
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- View/download PDF
5. Functional cooperation of the hedgehog and androgen signaling pathways during developmental and repairing myelination
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Yousra Laouarem, Pierre Bobé, Elisabeth Traiffort, Amine Mellouk, Michael Schumacher, Claudia Mattern, Tom Hutteau-Hamel, Amina Zahaf, and Abdelmoumen Kassoussi
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0301 basic medicine ,Regulatory T cell ,CNS demyelination ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Myelin ,0302 clinical medicine ,medicine ,Animals ,Hedgehog Proteins ,Testosterone ,Hedgehog ,Myelin Sheath ,Neuroinflammation ,FOXP3 ,Oligodendrocyte ,Hedgehog signaling pathway ,Cell biology ,Oligodendroglia ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Neuroinflammatory Diseases ,Androgens ,030217 neurology & neurosurgery ,Demyelinating Diseases ,Signal Transduction - Abstract
Hedgehog morphogens control fundamental cellular processes during tissue development and regeneration. In the central nervous system (CNS), Hedgehog signaling has been implicated in oligodendrocyte and myelin production, where it functions in a concerted manner with other pathways. Since androgen receptor (AR) plays a key role in establishing the sexual phenotype of myelin during development and is required for spontaneous myelin regeneration in the adult CNS, we hypothesized the existence of a possible coordination between Hedgehog and androgen signals in oligodendrocyte and myelin production. Here, we report complementary activities of both pathways during early postnatal oligodendrogenesis further revealing that persistent Hedgehog signaling activation impedes myelin production. The data also uncover prominent pro-myelinating activity of testosterone and involvement of AR in the control of neural stem cell commitment toward the oligodendroglial lineage. In the context of CNS demyelination, we provide evidence for the functional cooperation of the pathways leading to acceleration of myelin regeneration that might be related to their respective role on microglial and astroglial responses, higher preservation of axonal integrity, lower neuroinflammation, and functional improvement of animals in an immune model of CNS demyelination. Strong decreases of deleterious cytokines in the CNS (GM-CSF, TNF-α, IL-17A) and spleen (IL-2, IFN-γ) stand as unique features of the combined drugs while the potent therapeutic activity of testosterone on peripheral immune cells contributes to increase tolerogenic CD11c+ dendritic cells, reduce the clonal expansion of conventional CD4+ T cells and increase CD4+ Foxp3+ regulatory T cells. Altogether, these data might open promising perspectives for demyelinating diseases.
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- 2021
6. The Shh receptor Boc is important for myelin formation and repair
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Frédéric Charron, Elisabeth Traiffort, Amina Zahaf, Mary Zakaria, Olivier Pascual, Abdelmoumen Kassoussi, Ines Hristovska, Yousra Laouarem, Marie-Eve Mayeur, and Julien Ferent
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Male ,Neurofilament ,Blotting, Western ,Intermediate Filaments ,Receptors, Cell Surface ,Cuprizone ,Mice ,03 medical and health sciences ,Myelin ,0302 clinical medicine ,medicine ,Animals ,Hedgehog Proteins ,Axon ,Sonic hedgehog ,Molecular Biology ,Cells, Cultured ,Myelin Sheath ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Microglia ,biology ,Macrophages ,Cell Differentiation ,Oligodendrocyte ,Hedgehog signaling pathway ,Myelin basic protein ,Cell biology ,Mice, Inbred C57BL ,Oligodendroglia ,medicine.anatomical_structure ,nervous system ,Immunoglobulin G ,biology.protein ,030217 neurology & neurosurgery ,Demyelinating Diseases ,Developmental Biology - Abstract
Myelination leads to the formation of myelin sheaths surrounding neuronal axons and is crucial for function, plasticity and repair of the central nervous system (CNS). It relies on the interaction of the axons and the oligodendrocytes: the glial cells producing CNS myelin. Here, we have investigated the role of a crucial component of the Sonic hedgehog (Shh) signalling pathway, the co-receptor Boc, in developmental and repairing myelination. During development, Boc mutant mice display a transient decrease in oligodendroglial cell density together with delayed myelination. Despite recovery of oligodendroglial cells at later stages, adult mutants still exhibit a lower production of myelin basic protein correlated with a significant decrease in the calibre of callosal axons and a reduced amount of the neurofilament NF-M. During myelin repair, the altered OPC differentiation observed in the mutant is reminiscent of the phenotype observed after blockade of Shh signalling. In addition, Boc mutant microglia/macrophages unexpectedly exhibit the apparent inability to transition from a highly to a faintly ramified morphology in vivo. Altogether, these results identify Boc as an important component of myelin formation and repair.
- Published
- 2019
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