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Comparison of central and peripheral myelination. (a) Each oligodendrocyte in the CNS can extend cytoplasmic projections to form multiple, multi-layered myelin sheaths (pink) around different axons, whereas each SC in the PNS completely wraps around a single axon by laying down multiple layers of cell membrane, of which the innermost layers constitute the myelin sheath (purple). (b) There is typically one oligodendrocyte between two nodes of Ranvier, which is not covered by plasma membrane to allow action potentials to jump from node to node. (c) Compared to oligodendrocytes, SC myelinated axons possess thicker myelin sheaths. SCs also have an enlarged non-axonal domain due to the extra presence of the cytoplasm and nuclei, which is covered by the outermost layer, called the neurilemma.
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Myelin sheaths, by supporting axonal integrity and allowing rapid saltatory impulse conduction, are of fundamental importance for neuronal function. In response to demyelinating injuries in the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) migrate to the lesion area, proliferate and differentiate into new oligodendrocytes th...
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Significance
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Citations
... SCs are the most abundant glial cells of the PNS and ensheath either myelinating or unmyelinating peripheral nerve axons [119,120]. SCs are essential in maintaining conduction of electrical impulses along PNS axons, supporting nerve development and regeneration, and providing peripheral nerve axons metabolic and neurotrophic support [121]. DPN is one of the most common complications of diabetes, affecting more than half of the people suffering from diabetes during the course of the disease. ...
Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.
Graphical abstract
... Schwann cells (SCs) are specialized myelinating glial cells of the peripheral nervous system (PNS) [57][58][59] that support and protect peripheral neurons as well as play a central role in successful PN regeneration. From a vast body of research in the last 30 years, SC transplantation (SCT) has been demonstrated to be a promising therapeutic approach for repairing the damaged nervous system, including SCI [60], peripheral nerve injury (PNI) [61][62][63], and multiple sclerosis (MS) [64,65]. SCT provides numerous benefits after SCI, such as limiting tissue damage, modulating inflammation [66], and reducing cystic cavitation as well as providing growth substrates and secreting growth factors for axon regeneration and remyelination repair, all of which collectively improve outcomes in experimental SCI models [67,68]. ...
Exosomes are nanoscale-sized membrane vesicles released by cells into their extracellular milieu. Within these nanovesicles reside a multitude of bioactive molecules, which orchestrate essential biological processes, including cell differentiation, proliferation, and survival, in the recipient cells. These bioactive properties of exosomes render them a promising choice for therapeutic use in the realm of tissue regeneration and repair. Exosomes possess notable positive attributes, including a high bioavailability, inherent safety, and stability, as well as the capacity to be functionalized so that drugs or biological agents can be encapsulated within them or to have their surface modified with ligands and receptors to imbue them with selective cell or tissue targeting. Remarkably, their small size and capacity for receptor-mediated transcytosis enable exosomes to cross the blood–brain barrier (BBB) and access the central nervous system (CNS). Unlike cell-based therapies, exosomes present fewer ethical constraints in their collection and direct use as a therapeutic approach in the human body. These advantageous qualities underscore the vast potential of exosomes as a treatment option for neurological injuries and diseases, setting them apart from other cell-based biological agents. Considering the therapeutic potential of exosomes, the current review seeks to specifically examine an area of investigation that encompasses the development of Schwann cell (SC)-derived exosomal vesicles (SCEVs) as an approach to spinal cord injury (SCI) protection and repair. SCs, the myelinating glia of the peripheral nervous system, have a long history of demonstrated benefit in repair of the injured spinal cord and peripheral nerves when transplanted, including their recent advancement to clinical investigations for feasibility and safety in humans. This review delves into the potential of utilizing SCEVs as a therapy for SCI, explores promising engineering strategies to customize SCEVs for specific actions, and examines how SCEVs may offer unique clinical advantages over SC transplantation for repair of the injured spinal cord.
... Some leukodystrophies (LDs), such as x-adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), and Krabbe disease (GLD), involve both the destruction of existing myelin sheaths and a lack of myelin production (Van der Knapp et al., 2016). Myelin production is halted if there is a loss of oligodendrocytes and Schwann cells, myelin-producing cells of the central and peripheral nervous systems (Chen et al., 2021). Different therapeutic mechanisms might be needed to 1) prevent the loss of existing myelin and to 2) recover myelin-producing function (Li et al., 2018). ...
Alexander Disease (AxD) is a rare, heritable white matter condition, or leukodystrophy, that helps to understand how collaborative, translational research can identify therapeutic options in a complex illness. AxD is a rare disease, first described in 1949, that affects approximately one in 2.7 million births. The disease hinders the function of the central nervous system (CNS) through the biotoxic overproduction of protein aggregates which cause the deterioration of the myelin sheath. Given the extreme rarity of AxD, disease-specific research is relatively limited, and there is no disease-modifying treatment currently available. At present, a clinical trial is underway to examine the safety and efficacy of Ionis Pharmaceuticals’ ION373, an Antisense Oligonucleotide (ASO), that has reported success in preventing the progression of AxD in mouse models. This paper reviews the key components of AxD, therapeutic designs for AxD, and ultimately suggests future directions to optimize the therapeutic approach. This review also aims to promote rare disease awareness, as scientific progress for conditions like Alexander Disease is achieved through advocacy and promotion.
... 47,48 Although they are peripheral nerve-derived cells, various studies have shown that adding SCs to MCCs can promote remyelination when transplanted into the injured spinal cord. 49,50 In addition to the embedded SCs, ECs have two functions. First, the transplanted ECs increase the number of oligodendrocyte (OL) lineages. ...
... 16,23 Gi/o's activation is linked to increased egr-2 expression, a transcription regulatory factor highly expressed in migrating neural crest cells, and is essential for normal differentiation and maintenance of myelinating Schwann cells, which have been found to remyelinate in the CNS under certain conditions. 24,25 The increased expression upon heterocomplex formation may be what underlies the increased synaptogenesis seen upon psilocybin administration in rats. ...
Depression remains one the most commonly diagnosed mental health disorders in the United States. The Food and Drug Administration granted psilocybin breakthrough therapy status four years ago as a possible solution to this pervasive disorder. Since then, psilocybin, and hallucinogens in general, have produced promising results as alternatives to classical antidepressants. As more research confirms psilocybin’s potential therapeutic effect, research surrounding the mechanistic action of these 5-HT2A receptor agonists has increased as well. Hallucinogens have different downstream effects compared to non-hallucinogenic 5-HT2A receptor agonists, including the formation of a 5-HT2A receptor and metabotropic glutamate receptor complex. Psilocybin’s unique synaptogenic effect may play a role in its therapeutic effect for major depressive disorder; however, the underlying mechanism by which synaptogenesis is induced upon psilocybin administration has not been explored. Psilocybin’s distinctive upregulation of transcription factors, such as egr-2, c-fos, and brain-derived neurotrophic factors, and its connection with the TrkB signaling pathway, may be the answer to this unexplained mechanism.
... Unlike the CNS, the PNS has the innate ability to regenerate and remyelinate mainly because of the contribution and plasticity of Schwann cells, which can dedifferentiate (Kumar et al., 2007;Johnston et al., 2016;Jessen and Arthur-Farraj, 2019). Therefore, taking advantage of the potential of Schwann cells to promote regeneration and remyelination in the CNS has become an innovative strategy for many research groups and Schwann cells are now thought of as promising rescuers of central demyelination (Zujovic and Van Evercooren, 2012;Garcia-Diaz and Baron-Van Evercooren, 2020;Chen et al., 2021). ...
The central and peripheral nervous systems (CNS and PNS, respectively) are two separate yet connected domains characterized by molecularly distinct cellular components that communicate via specialized structures called transition zones to allow information to travel from the CNS to the periphery, and vice versa. Until recently, nervous system transition zones were thought to be selectively permeable only to axons, and the establishment of the territories occupied by glial cells at these complex regions remained poorly described and not well understood. Recent work now demonstrates that transition zones are occupied by dynamic glial cells and are precisely regulated over the course of nervous system development. This review highlights recent work on glial cell migration in and out of the spinal cord, at motor exit point (MEP) and dorsal root entry zone (DREZ) transition zones, in the physiological and diseased nervous systems. These cells include myelinating glia (oligodendrocyte lineage cells, Schwann cells and motor exit point glia), exit glia, perineurial cells that form the perineurium along spinal nerves, as well as professional and non-professional phagocytes (microglia and neural crest cells).
... Both parenchymal oligodendrocyte precursor cells (OPCs), a population of widespread resident adult multipotent progenitors that comprise 5% of total brain cells , and neural stem cells (NSCs) located within the germinal niche can generate such new oligodendrocytes. Moreover, even Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), were revealed to contribute to this CNS regenerative response (reviewed by Chen et al., 2021). Briefly, OPCs migrate to lesion sites (Levine and Reynolds, 1999), (eventually) proliferate (Choi et al., 2018) and predominantly differentiate into new myelin-forming oligodendrocytes. ...
Astrocytes are indispensable for central nervous system development and homeostasis. In response to injury and disease, astrocytes are integral to the immunological- and the, albeit limited, repair response. In this review, we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models. We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination. Finally, we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.
... One such marker is the transcription factor Sox10, which is expressed in OPCs and their progeny, as well as in Schwann cells (Stolt et al., 2002). Schwann cells are a type of glial cells that normally myelinates peripheral nerves but can also contribute to remyelination in the CNS (Chen et al., 2021). Other molecular markers of remyelination include growth factors and cytokines that regulate the proliferation and differentiation of OPCs. ...
Remyelination relies on the repair of damaged myelin sheaths, involving microglia cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes. This process drives the pathophysiology of autoimmune chronic disease of the central nervous system (CNS), multiple sclerosis (MS), leading to nerve cell damage and progressive neurodegeneration. Stimulating the reconstruction of damaged myelin sheaths is one of the goals in terms of delaying the progression of MS symptoms and preventing neuronal damage. Short, noncoding RNA molecules, microRNAs (miRNAs), responsible for regulating gene expression, are believed to play a crucial role in the remyelination process. For example, studies showed that miR-223 promotes efficient activation and phagocytosis of myelin debris by microglia, which is necessary for the initiation of remyelination. Meanwhile, miR-124 promotes the return of activated microglia to the quiescent state, while miR-204 and miR-219 promote the differentiation of mature oligodendrocytes. Furthermore, miR-138, miR-145, and miR-338 have been shown to be involved in the synthesis and assembly of myelin proteins. Various delivery systems, including extracellular vesicles, hold promise as an efficient and non-invasive way for providing miRNAs to stimulate remyelination. This article summarizes the biology of remyelination as well as current challenges and strategies for miRNA molecules in potential diagnostic and therapeutic applications.
... aOPC reactivity is prominent in traumatic injury and neuroinflammation, and is manifested by two distinct phenotypes: cellular hypertrophy or cell transformation into bipolar migratory cells that resemble fetal OPCs. There is some evidence that reactive aOPCs may transform, in some pathological contexts, into other glia or even neurons [1,57]; some aOPCs were even claimed to transform into Schwann cells to assist remyelination [58]. This phenomenon is referred to as 'transdifferentiation'. ...
Adult oligodendrocyte precursor cells (aOPCs), transformed from fetal OPCs, are idiosyncratic neuroglia of the central nervous system (CNS) that are distinct in many ways from other glial cells. OPCs have been classically studied in the context of their remyelinating capacity. Recent studies, however, revealed that aOPCs not only contribute to post-lesional remyelination but also play diverse crucial roles in multiple neurological diseases. In this review we briefly present the physiology of aOPCs and summarize current knowledge of the beneficial and detrimental roles of aOPCs in different CNS diseases. We discuss unique features of aOPC death, reactivity, and changes during senescence, as well as aOPC interactions with other glial cells and pathological remodeling during disease. Finally, we outline future perspectives for the study of aOPCs in brain pathologies which may instigate the development of aOPC-targeting therapeutic strategies.
... Here, we provide an overview of the known roles of terminal SCs at the NMJ and in the skin and discuss the function of satellite and enteric glial cells. For the role of SCs in the CNS, as well as for olfactory ensheathing cells, we refer the reader to respective reviews on this topic(Chen et al., 2021;Reed et al., 2021;Stierli et al., 2019;Ursavas et al., 2021).M.Bosch-Queralt et al. ...
The glial cell of the peripheral nervous system (PNS), the Schwann cell (SC), counts among the most multifaceted cells of the body. During development, SCs secure neuronal survival and participate in axonal path finding. Simultaneously, they orchestrate the architectural set up of the developing nerves, including the blood vessels and the endo-, peri- and epineurial layers. Perinatally, in rodents, SCs radially sort and subsequently myelinate individual axons larger than 1 μm in diameter, while small calibre axons become organised in non-myelinating Remak bundles. SCs have a vital role in maintaining axonal health throughout life and several specialized SC types perform essential functions at specific locations, such as terminal SC at the neuromuscular junction (NMJ) or SC within cutaneous sensory end organs. In addition, neural crest derived satellite glia maintain a tight communication with the soma of sensory, sympathetic, and parasympathetic neurons and neural crest derivatives are furthermore an indispensable part of the enteric nervous system. The remarkable plasticity of SCs becomes evident in the context of a nerve injury, where SC transdifferentiate into intriguing repair cells, which orchestrate a regenerative response that promotes nerve repair. Indeed, the multiple adaptations of SCs are captivating, but remain often ill-resolved on the molecular level. Here, we summarize and discuss the knowns and unknowns of the vast array of functions that this single cell type can cover in peripheral nervous system development, maintenance, and repair.
