Biology subjects

Nait Oumesmar, B.

Publications and source records attributed to Nait Oumesmar, B..

4 recordsLinked to original sources

bioRxiv2026

Development of a Humanized Mouse Model for Studying adult Spinal Cord myelination, remyelination and Drug Efficacy

Oligodendrocytes are essential for central nervous system (CNS) function through their roles in myelination and neuronal support. Remyelination, the regeneration of myelin after damage, often fails in human demyelinating diseases, leading to progressive neurological dysfunction. While the biology of rodent oligodendroglia has been investigated in depth, species-specific differences have hindered the study of human oligodendrocyte progenitor cells maturation using current animal models. To address this gap, we developed a humanized oligodendroglia chimeric mouse model by transplanting human iPSC-derived O4+ oligodendroglial progenitors (hiOLs) into the developing spinal cord of myelin deficient-immunosuppressed mice followed by demyelination of the adult humanized spinal cord. This paradigm allows in vivo investigation of hiOL fate during their maturation and ageing, and the response of their settled progeny to demyelinating injury. Following transplantation during postnatal development, hiOLs proliferated, migrated, and differentiated into mature oligodendrocytes, initiating axonal myelination. A population of undifferentiated, proliferative adult human oligodendrocyte progenitors presisted, indicating a reservoir of these cells capable of responding to injury. Spinal cord focal demyelination via lysolecithin injection in the adult humanized spinal cord led to transient loss of human-derived mature oligodendrocytes and myelin, followed by myelin recovery together with endogenous cells. Treatment with the histamine receptor H3 antagonist, bavisant, a recently identified promyelinating compound, significantly enhanced hiOL maturation and myelin production, indicating promotion of their differentiation when administered post-demyelination. Electron microscopy showed an increased number of human-derived remyelinated axons together with decreased g-ratios in bavisant treated animals. This humanized spinal cord model of myelination/demyelination-remyelination faithfully recapitulates key aspects of human oligodendrocyte biology and CNS repair, providing a powerful tool to study human-specific myelination and remyelination mechanisms and screen for emerging remyelinating therapies. Its application in disease modeling and preclinical testing holds promise for advancing personalized treatments in demyelinating and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Monocarboxylate transporter 2 is required for the maintenance of myelin and axonal integrity by oligodendrocytes

Neurodegenerative pathologies including multiple sclerosis (MS) are consistently associated with energy deficit in the central nervous system (CNS). This might directly impact myelinating oligodendrocytes as these are particularly vulnerable to metabolic insults. Importantly, oligodendroglial dysfunction and myelin alterations occur in most, if not all neurodegenerative diseases, and are associated with axonal pathology/loss. Thus, elucidating metabolic mechanisms required for oligodendroglial myelin maintenance and axonal support might be crucial to identify therapeutic targets to achieve neuroprotection. While monocarboxylates are important energy fuels for the CNS, their role in myelinating oligodendrocyte function remains unclear. Here we show that, just like neurons, myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2) both in mice and humans, which is downregulated in progressive MS. While deletion of MCT2 in mouse oligodendrocytes did not affect the survival of these cells, it resulted in downregulation of lipid synthesis-associated enzymes and failure of myelin maintenance. Moreover, axonal upregulation of lactate dehydrogenase A concomitant with axonal damage was observed but could be alleviated by ketogenic diet. We conclude that oligodendroglial MCT2 is required for myelin maintenance and axonal support, which becomes altered in progressive MS, but may be compensated for by specific metabolic therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/632306v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@2b7b22org.highwire.dtl.DTLVardef@a111fdorg.highwire.dtl.DTLVardef@a410f5org.highwire.dtl.DTLVardef@1556e2f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts the axon, while a drastic shift to actin depolymerization is required to enable the following step of wrapping and expansion of myelin membranes. The molecular mechanisms triggering this switch, essential for proper myelination, have yet to be elucidated. Here, we identify P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. We show that PAK1 accumulates in OLs in a kinase inhibited form, triggering actin disassembly and, consequently, myelin expansion. Remarkably, we identify NF2/Merlin as an endogenous inhibitor of PAK1 by proteomics analysis of its binding partners. We found that Nf2 knockdown in OLs results in PAK1 activation and impairs myelin formation, and that pharmacological inhibition of PAK1 in Nf2-knockdown OLs rescues these defects. Moreover, we demonstrate that modulating PAK1 activity in OLs controls myelin expansion and provide compelling evidence indicating that specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that PAK1-NF2/Merlin duo plays a key role in actin cytoskeleton remodeling in OLs, required for proper myelin formation. These findings have broad mechanistic and therapeutic implications for demyelinating diseases and neurodevelopmental disorders. SignificanceRemodeling actin cytoskeleton plays a crucial role in myelin formation by oligodendrocytes (OLs). Recent studies have shown that expansion and wrapping of myelin membranes around axons depends on actin depolymerization. However, the molecular mechanisms triggering this key step in myelination are not fully elucidated. Using genetic and pharmacological tools as well as proteomics analyses, we found that PAK1 (P21 Activated Kinase 1) kinase activity is maintained inhibited by NF2/Merlin in OLs to allow actin depolymerization and, consequently, myelin membrane expansion. Pak1 loss-of-function in OLs leads to an increase in myelin thickness in the white matter of adult mice, confirming the role of PAK1 inactivation in myelin membrane expansion.

neuroscience↗

bioRxiv2021

Reduced axon caliber in the associative striatum of the Sapap3 knockout mouse

Pathological repetitive behaviors are a common feature of different neuropsychiatric disorders such as obsessive-compulsive disorder or Gilles de la Tourette syndrome. The Sapap3 knockout mouse (Sapap3-KO) is the current reference model used in translational psychiatry to study co-morbid repetitive behaviors, presenting both compulsive-like as well as tic-like behaviors. Consistent with clinical and fundamental research literature relating compulsive-like symptoms to associative cortico-striatal dysfunctions and tic-like symptoms to sensorimotor cortico-striatal dysfunctions, abnormalities comprising both circuits have been described in this mouse model. Findings reported on these mice point towards not only macro-, but also micro-circuitry deficits, both of which can be affected by neuronal structural changes. As such, in the present study, we aimed to investigate structural changes in associative and sensorimotor striatal areas that could affect information conduction. We used AxonDeepSeg, an open-source software to automatically segment and measure myelin thickness and axon caliber, and found that axon caliber, the main contributor for changes in conduction speed, is specifically reduced in the associative but not the sensorimotor striatum of the Sapap3-KO mouse. This smaller axon caliber in Sapap3-KO mice is not a general neuronal feature of this region, but specific to a subpopulation of axons with large caliber. These results point to a primary structural deficit in the associative striatum, affecting signal conduction and consequent connectivity.

neuroscience↗