DNA methylation in Schwann cells and in oligodendrocytes.

DNA methylation is one of many epigenetic marks, which directly modifies base residues, usually cytosines, in a multiple-step cycle. It has been linked to the regulation of gene expression and alternative splicing in several cell types, including during cell lineage specification and differentiation processes. DNA methylation changes have also been observed during aging, and aberrant methylation patterns have been reported in several neurological diseases. We here review the role of DNA methylation in Schwann cells and oligodendrocytes, the myelin-forming glia of the peripheral and central nervous systems, respectively. We first address how methylation and demethylation are regulating myelinating cells' differentiation during development and repair. We then mention how DNA methylation dysregulation in diseases and cancers could explain their pathogenesis by directly influencing myelinating cells' proliferation and differentiation capacities

Genetically modified macrophages accelerate myelin repair

[EN] Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination. However, molecular targeting to MS lesions is a challenge. A clinically relevant paradigm for delivering Sema3F to demyelinating lesions could be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically modified hematopoietic stem cells (HSCs) as means of obtaining chimeric mice with circulating Sema3F-overexpressing monocytes. We demonstrated that Sema3F-transduced HSCs stimulate OPC migration in a neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion, which was conserved in middle-aged OPCs. While demyelinating lesions induced in mice with Sema3F-expressing blood cells showed no changes in inflammation and OPC survival, OPC recruitment was enhanced which accelerated the onset of remyelination. Our results provide a proof of concept that blood cells, particularly monocytes/macrophages, can be used to deliver pro-remyelinating agents "at the right time and place," suggesting novel means for remyelination-promoting strategies in MS.This work was supported by the French National Institute of Health and Medical Research (INSERM), French National Research Agency (ANR, project Stemimus ANR-12-BSV4-0002-02), the European Leukodystrophy Association (ELA, project 2016-004C5B), NeurATRIS, the program "Investissements d'avenir" (ANR-10-IAIHU-06), CIBERNED (CB06/0005/0076), and Gobierno Vasco (IT1203-19). VT was a recipient of the Spanish Ministry of Economy Young Investigator Grant (SAF2015-74332-JIN)

Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS

Correction: Pruvost, M.; Moyon, S. Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination. <i>Life</i> 2021, <i>11</i>, 62

The authors wish to make the following corrections to this paper [...

Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination

Oligodendroglial cells are the myelinating cells of the central nervous system. While myelination is crucial to axonal activity and conduction, oligodendrocyte progenitor cells and oligodendrocytes have also been shown to be essential for neuronal support and metabolism. Thus, a tight regulation of oligodendroglial cell specification, proliferation, and myelination is required for correct neuronal connectivity and function. Here, we review the role of epigenetic modifications in oligodendroglial lineage cells. First, we briefly describe the epigenetic modalities of gene regulation, which are known to have a role in oligodendroglial cells. We then address how epigenetic enzymes and/or marks have been associated with oligodendrocyte progenitor specification, survival and proliferation, differentiation, and finally, myelination. We finally mention how environmental cues, in particular, neuronal signals, are translated into epigenetic modifications, which can directly influence oligodendroglial biology

Influence de la démyélinisation et du vieillissement sur le profil d expression génique des cellules progénitrices d oligodendrocytes adultes (vers l identification de nouveaux signaux moléculaires favorisant la réparation myélinique)

La remyélinisation du système nerveux central (SNC) est un processus régénératif spontané pendant lequel les cellules progénitrices d oligodendrocytes adultes (aOPCs), en réponse à une démyélinisation, subissent des changements d'expression génique, permettant leur prolifération, migration et différenciation en nouveaux oligodendrocytes (OLs) myélinisants. La baisse des capacités de remyélinisation dans des maladies comme la sclérose en plaques (SEP), a stimulé la recherche de mécanismes par lesquels elle pourrait être favorisée. Notre étude transcriptomique a démontré que les aOPCs ont un profil d'expression génique différent au cours du vieillissement et plus mature que les OPCs néonataux, leur profil étant plus proche de ceux des OLs. Nous avons montré qu en réponse à une démyélinisation expérimentale, les aOPCs ré-expriment un profil transcriptomique immature, et acquièrent des capacités de migration et de différenciation plus rapides. Parmi les nombreux gènes différenciellement exprimés par ces aOPCs activés, nous nous sommes concentrés sur des gènes de molécules de guidage et de la réponse immunitaire innée, et démontré que l'augmentation de leur expression est corrélée avec une modification des capacités de migration des aOPCs, paramètre crucial pour la réparation myélinique. L'expression accrue de ces molécules par les aOPCs a été confirmée dans des modèles expérimentaux et dans des lésions de SEP, renforçant l'importance physiopathologique de nos résultats. Ces résultats ouvrent de nouvelles perspectives sur l activation des aOPCs, et sur le rôle de l interaction entre les cellules gliales et les cellules du système immunitaire, lors de la démyélinisation.Central nervous system (CNS) remyelination is a spontaneous regenerative process in which adult oligodendrocyte progenitor cells (aOPCs) respond to demyelination by undergoing changes in their pattern of gene expression enabling them to divide, migrate and then differentiate into new myelin sheath-forming oligodendrocytes (OLs). The declining efficiency of this regenerative process in diseases such as multiple sclerosis (MS) has stimulated a search for ways by which it might be therapeutically enhanced. Our transcriptomic study has demonstrated that aOPCs have a different gene expression profile during aging and a more mature profile than neonatal OPCs, their profile being closer to the one of OLs. We have showed that, in response to cuprizone-induced demyelination, aOPCs revert to an immature gene expression profile, acquiring faster migration and differentiation capacities. Among the many genes differentially regulated by these demyelination-activated aOPCs, we have focused on genes of the guidance cues and of the innate immune response and demonstrated that their increased expression correlates with increased migration capacities of aOPCs, a crucial parameter for early myelin repair. Increased expression of these molecules has been confirmed in both experimental model and MS, further strengthening the pathophysiological significance of our results. These results open new openings on what distinguishes non-activated and activated aOPCs, with a new perspective on induced immune-glial interactions and its role on aOPCs recruitment.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

DNA methylation in Schwann cells and in oligodendrocytes

International audienceDNA methylation is one of many epigenetic marks, which directly modifies base residues,usually cytosines, in a multiple-step cycle. It has been linked to the regulationof gene expression and alternative splicing in several cell types, including during celllineage specification and differentiation processes. DNA methylation changes havealso been observed during aging, and aberrant methylation patterns have beenreported in several neurological diseases. We here review the role of DNA methylationin Schwann cells and oligodendrocytes, the myelin-forming glia of the peripheraland central nervous systems, respectively. We first address how methylation anddemethylation are regulating myelinating cells' differentiation during developmentand repair. We then mention how DNA methylation dysregulation in diseases andcancers could explain their pathogenesis by directly influencing myelinating cells' proliferationand differentiation capacities

Neural stem cells and oligodendrocyte progenitor cells compete for remyelination in the corpus callosum

International audienceA major therapeutic goal in demyelinating diseases, such as Multiple Sclerosis, is to improve remyelination, thereby restoring effective axon conduction and preventing neurodegeneration. In the adult central nervous system (CNS), parenchymal oligodendrocyte progenitor cells (pOPCs) and, to a lesser extent, pre-existing oligodendrocytes (OLs) and oligodendrocytes generated from neural stem cells (NSCs) in the sub-ventricular zone (SVZ) are capable of forming new myelin sheaths. Due to their self-renewal capabilities and the ability of their progeny to migrate widely within the CNS, NSCs represent an additional source of remyelinating cells that may be targeted to supplement repair by pOPCs. However, in demyelinating disorders and disease models, the NSC contribution to myelin repair is modest and most evident in regions close to the SVZ. We hypothesized that NSC-derived cells may compete with OPCs to remyelinate the same axons, with pOPCs serving as the primary remyelinating cells due to their widespread distribution within the adult CNS, thereby limiting the contribution of NSC-progeny. Here, we have used a dual reporter, genetic fate mapping strategy, to characterize the contribution of pOPCs and NSC-derived OLs to remyelination after cuprizone-induced demyelination. We confirmed that, while pOPCs are the main remyelinating cells in the corpus callosum, NSC-derived cells are also activated and recruited to demyelinating lesions. Blocking pOPC differentiation genetically, resulted in a significant increase in the recruitment NSC-derived cells into the demyelinated corpus callosum and their differentiation into OLs. These results strongly suggest that pOPCs and NSC-progeny compete to repair white matter lesions. They underscore the potential significance of targeting NSCs to improve repair when the contribution of pOPCs is insufficient to affect full remyelination

Epigenetics in NG2 glia cells

International audienceThe interplay of transcription and epigenetic marks is essential for oligodendrocyte progenitor cell (OPC) proliferation and differentiation during development. Here, we review the recent advances in this field and highlight mechanisms of transcriptional repression and activation involved in OPC proliferation, differentiation and plasticity. We also describe how dysregulation of these epigenetic events may affect demyelinating disorders, and consider potential ways to manipulate NG2 cell behavior through modulation of the epigenome