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Activation of P2X7R Inhibits Proliferation and Promotes the Migration and Differentiation of Schwann Cells.

In the vertebrate nervous system, myelination of nerve fibers is crucial for the rapid propagation of action potentials through saltatory co … ession. In vivo experiments showed that the activation of P2X7R using an agonist injection promoted remyelination, while the antagonists hindered remyelination. Further, in vitro experiments supported these findings and demonstrated that P2X7R activation inhibited the proliferation of Schwann cells, but it promoted the migration and differentiation of the Schwa …

The Morphofunctional Effect of the Transplantation of Bone Marrow Stromal Cells and Predegenerated Peripheral Nerve in Chronic Paraplegic Rat Model via Spinal Cord Transection.

Functional recovery following spinal cord injury (SCI) is limited by poor axonal and cellular regeneration as well as the failure to replace damaged myelin. Employed separately, both the transplantation of the predegenerated peripheral nerve (PPN) and the transplantation of bone marrow stromal cells (BMSCs) have been shown to promote the regrowth and remyelination of the damaged central axons in SCI models of hemisection, transection, and contusion injury. With the aim to test the effects of the combined transplantation of PPN and BMSC on regrowth, remyelination, and locomotor function in an a…

Неоднородный перенос магнитизации (ihMT) показывает изменяющиеся характеристики восстановления активных повреждений MS в зависимости от размера и локализации.

Эта работа направлена на использование уникальной миелинской специфичности метода неоднородной магнитизации (ihMT) для характеристики динамики восстановления активных множественных склерозов (MS). В ходе 12-месячного продольного исследования, проведенного в отношении вновь излучающих рассеяние пациентов, были применены IhMT и три других чувствительных к миелину методов, обычные МТ, Т1, взвешенные и диффузионные снимки tensor. Модель экспоненциального восстановления использовалась для учета вариаций с течением времени параметров, полученных с помощью каждого метода MR в рамках новых активных по

Совпадение в аннотации оригинала
This work aims at exploiting the unique myelin specificity of the inhomogeneous magnetization transfer (ihMT) technique to characterize the … to the specificity of the ihMT technique for myelin, these features can be interpreted in terms of remyelination. This study thus provides longitudinal in vivo support for the pathological observations of higher remyelination in small lesions compared with large ones and faster remyelination in lesions away from the ventricles. These results support the use of …

The effect of microglial ablation and mesenchymal stem cell transplantation on a cuprizone-induced demyelination model.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system with symptoms such as neuroinflammation, astrocytosis, microgliosis, and axonal degeneration. Mesenchymal stem cells (MSCs) with their immunomodulation, differentiation, and neuroprotection abilities can influence the remyelination process. The goal of this study is to investigate the impact of microglial ablation and MSCs transplantation on remyelination processes in the corpus callosum (CC) of the cuprizone demyelination model. For the induction of a chronic demyelination model, C57BL6 mice were fed w…

The response of the (myelinating) Schwann cell population to multiple episodes of demyelination.

The effects of multiple intraneural injections of the known demyelinating agent lysophosphatidyl choline, LPC, have been studied in the sciatic nerves of adult mice. Up to six separate episodes of demyelination were induced at the same site within the tibial fascicle. Demyelination and subsequent remyelination occurred after each injection. The number of Schwann cells produced during each repair programme exceeded the number required for remyelination and some of the surplus cells temporarily remained associated with the remyelinating axon/Schwann cell units as supernumerary Schwann cells. The…

Growth Differentiation Factor 11 Is a Circulating Regulator of Oligodendrocyte Differentiation and CNS Myelin Formation and Repair.

AIMS: Remyelination failure is a major contributor to progressive neurological disability in multiple sclerosis (MS). Although oligodendrocyte progenitor cells (OPCs) persist in demyelinated lesions, they often fail to differentiate into myelinating oligodendrocytes. This study aimed to determine whether growth differentiation factor 11 (GDF11), a circulating member of the TGF-β superfamily, regulates oligodendrocyte differentiation, CNS myelination, and remyelination. METHODS: The effects of GDF11 were examined using purified mouse OPC cultures, a neonatal developmental myelination model, an…

Gpr126/Adgrg6 Has Schwann Cell Autonomous and Nonautonomous Functions in Peripheral Nerve Injury and Repair.

UNLABELLED: Schwann cells (SCs) are essential for proper peripheral nerve development and repair, although the mechanisms regulating these processes are incompletely understood. We previously showed that the adhesion G protein-coupled receptor Gpr126/Adgrg6 is essential for SC development and myelination. Interestingly, the expression of Gpr126 is maintained in adult SCs, suggestive of a function in the mature nerve. We therefore investigated the role of Gpr126 in nerve repair by studying an inducible SC-specific Gpr126 knock-out mouse model. Here, we show that remyelination is severely delaye…

Therapeutic Effects of Combined 6-Shogaol and Ibudilast on Neuroinflammation and Behavioral Deficits in a Cuprizone Mouse Model of Multiple Sclerosis.

Background/Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by inflammation, … ce were exposed to 0.3% CPZ for 5 weeks to induce demyelination, followed by 4 weeks of spontaneous remyelination after CPZ withdrawal. During remyelination, the CPZ group was subdivided into four groups: no therapy, SH (25 mg/kg), IBD (10 mg/kg), and SH + IBD. Behavioral tests were used to assess locomotion, muscle strength, coordination, and memory. Gene expr …

Ninj2 regulates Schwann cells development by interfering laminin-integrin signaling.

Rationale: Myelin sheath is an important structure to maintain normal functions of the nerves. Nerve Injury-Induced Protein 2 (Ninj2) was found upregulated in Schwann cells (SC) upon injury. However, whether and how Ninj2 plays a role in myelination remain unknown. Methods: In this study, we use transmission electron microscope imaging, immunofluorescent imaging, and behavioral tests to show the effects of Ninj2 on myelination and remyelination in peripheral nervous system (PNS) of SC-specific Ninj2 knockout mice (Dhhcre/+;Ninj2fl/fl ). For mechanism studies, we use RNA-Seq analysis to show th…

Aged oligodendrocyte progenitors retain the capacity to respond to an inflammatory insult.

Aging is associated with neurodegeneration and progressive disability in people living with multiple sclerosis (MS). Aged oligodendrocyte progenitor cells (OPCs) exhibit slower differentiation and remyelination coupled with upregulation of senescence pathways, both in physiological aging and toxin-mediated murine models. The impact of auto-immune demyelinating environment on young and aged OPCs has not been explored. This study combined a genetic OPC lineage tracing approach in young and middle-aged animals with adoptive transfer of MOG-reactive Th17 T cells to determine how aging influences O…

GD1a Overcomes Inhibition of Myelination by Fibronectin via Activation of Protein Kinase A: Implications for Multiple Sclerosis.

Remyelination failure by oligodendrocytes contributes to the functional impairment that characterizes the demyelinating disease multiple sclerosis (MS). Since incomplete remyelination will irreversibly damage axonal connections, treatments effectively promoting remyelination are pivotal in halting disease progression. Our previous findings suggest that fibronectin aggregates, as an environmental factor, contribute to remyelination failure by perturbing oligodendrocyte progenitor cell (OPC) maturation. Here, we aim at elucidating whether exogenously added gangliosides (i.e., cell surface lipids…

In silico screening and preclinical validation identify bavisant as a therapeutic candidate for multiple sclerosis.

Current treatments for multiple sclerosis (MS) are insufficient to delay the neurodegenerative process that is the main cause of disability progression in patients with MS. Therapeutics aimed at supporting myelin regeneration and neuroprotection are thus a major unmet medical need for the progressive forms of MS. To address this, we developed a strategy combining in silico screening of more than 1500 repurposed compounds with a validation pipeline of models, encompassing rodent and human in vitro assays as well as mouse models of demyelination/remyelination. From the initial library, 273 drugs…

Repeated ablations of mature Tmem10+ oligodendrocytes recapitulates key pathological features of multiple sclerosis with prolonged demyelination.

Managing multiple sclerosis (MS), a chronic, neuroinflammatory and demyelinating disease, remains an unmet medical need. A great obstacle to developing therapeutic interventions altering the disease process is the lack of a suitable disease model recapitulating its core pathologies, especially the process of myelin damage and regeneration against the backdrop of persistent neuroinflammation. Now we report the generation and characterization of a new demyelination/remyelination model with key pathological features of MS through repeated ablations of Tmem10+ oligodendrocytes. Using the Tmem10-Cr…

Spatial and temporal profiles of growth factor expression during CNS demyelination reveal the dynamics of repair priming.

Demyelination is the cause of disability in various neurological disorders. It is therefore crucial to understand the molecular regulation of oligodendrocytes, the myelin forming cells in the CNS. Growth factors are known to be essential for the development and maintenance of oligodendrocytes and are involved in the regulation of glial responses in various pathological conditions. We employed the well established murine cuprizone model of toxic demyelination to analyze the expression of 13 growth factors in the CNS during de- and remyelination. The temporal mRNA expression profile during demye…

VEGF- and PDGF-dependent proliferation of oligodendrocyte progenitor cells in the medulla oblongata after LPC-induced focal demyelination.

The myelin sheath is critical in maintaining normal functions of the adult central nervous system (CNS) and the loss of the myelin sheath results in various neurological diseases. Although remyelination is the intrinsic repair system against demyelination that new myelin sheath is formed around axons in the adult CNS, little has been reported on remyelination system in the medulla oblongata. In the present study, we showed that the proliferation of oligodendrocyte progenitor cells (OPCs) was increased in the medulla oblongata by lysophosphatidylcholine (LPC)-induced focal demyelination, but th…

A human-induced pluripotent stem cell-derived spheroid model to investigate myelin injury and repair.

There are no currently approved therapies that promote new myelin formation after myelin damage, which can, in part, be attributed to a lack of reliable systems that can reproducibly model these processes. Here we engineered a human iPSC-derived spheroid model enriched with mature, myelinating oligodendrocytes and functionally reactive microglia. This model enables the study of human central nervous system remyelination after a demyelinating insult by recapitulating processes of myelin damage and repair. These include myelin fragmentation, microglial reactivity and phagocytosis of myelin debri…

Neutral Red Labeling: A Novel Vital Staining Method for Investigating Central and Peripheral Nervous System Lesions.

Multiple sclerosis, neuromyelitis optica, Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy are representative demyelinating diseases of the central and peripheral nervous system. Remyelination by myelin forming cells is important for functional recovery from the neurological deficits caused in the demyelinating diseases. Lysophosphatidylcholine-induced demyelination in mice is commonly used to identify and study the molecular pathways of demyelination and remyelination. However, detection of focally demyelinated lesions is difficult and usually requires sec…

Cuprizone feeding induces swollen astrocyte endfeet.

The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is mainly being used to study demyelination and the mechanisms of remyelination, as well as the efficiency of compounds or therapeutics aiming at remyelination. Although early investigations using high dosages of cuprizone reported the occurrence of hydrocephalus, it has long been assumed that cuprizone feeding at lower dosages does not induce changes at the blood-brain barrier (BBB). Here, by analyzing BBB ultrastructure with high…

An autopsied case of the Crow-Fukase syndrome: a neuropathological study with emphasis on spinal roots.

An autopsied case of the Crow-Fukase syndrome is reported. Neuropathological findings were as follows: (1) in the sural nerve, there was marked decrease of large and small myelinated fibers. Myelinated fibers showing axonal degeneration and segmental demyelination and remyelination were moderately increased. (2) In the lumbar spinal roots, myelinated fibers showing segmental demyelination and remyelination were frequently observed. The density of myelinated fibers of the ventral root was less at the dural site than the spinal site, while that of the dorsal roots was less at the spinal site tha…

Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination.

Impaired myelin repair, or remyelination, is a hallmark of progressive multiple sclerosis (MS) that drives brain degeneration and enduring neurological disabilities. Microglia crucially support remyelination through myelin phagocytosis and lipid metabolism. However, in chronic demyelinated MS lesions, microglia lose their reparative function by acquiring a foamy dysfunctional phenotype characterized by accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Here, we show a positive correlation between dysregulation of neuregulin-1 and impaired oligodendrocyte re…