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International Journal of Molecular... Nov 2018Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune... (Review)
Review
Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.
Topics: Animals; Central Nervous System; Cholesterol; Demyelinating Diseases; Humans; Recovery of Function; Signal Transduction; Smoothened Receptor
PubMed: 30463396
DOI: 10.3390/ijms19113677 -
CNS Neuroscience & Therapeutics Dec 2020Demyelination occurs in response to brain injury and is observed in many neurodegenerative diseases. Myelin is synthesized from oligodendrocytes in the central nervous... (Review)
Review
Demyelination occurs in response to brain injury and is observed in many neurodegenerative diseases. Myelin is synthesized from oligodendrocytes in the central nervous system, and oligodendrocyte death-induced demyelination is one of the mechanisms involved in white matter damage after stroke and neurodegeneration. Oligodendrocyte precursor cells (OPCs) exist in the brain of normal adults, and their differentiation into mature oligodendrocytes play a central role in remyelination. Although the differentiation and maturity of OPCs drive endogenous efforts for remyelination, the failure of axons to remyelinate is still the biggest obstacle to brain repair after injury or diseases. In recent years, studies have made attempts to promote remyelination after brain injury and disease, but its cellular or molecular mechanism is not yet fully understood. In this review, we discuss recent studies examining the demyelination process and potential therapeutic strategies for remyelination in aging and stroke. Based on our current understanding of the cellular and molecular mechanisms underlying remyelination, we hypothesize that myelin and oligodendrocytes are viable therapeutic targets to mitigate brain injury and to treat demyelinating-related neurodegeneration diseases.
Topics: Aging; Animals; Brain; Central Nervous System; Demyelinating Diseases; Humans; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; Stroke
PubMed: 33210839
DOI: 10.1111/cns.13497 -
Scientific Reports Aug 2021Lysophosphatidylcholine (LPC)-induced demyelination is a versatile animal model that is frequently used to identify and examine molecular pathways of demyelination and...
Lysophosphatidylcholine (LPC)-induced demyelination is a versatile animal model that is frequently used to identify and examine molecular pathways of demyelination and remyelination in the central (CNS) and peripheral nervous system (PNS). However, identification of focally demyelinated lesion had been difficult and usually required tissue fixation, sectioning and histological analysis. Recently, a method for labeling and identification of demyelinated lesions in the CNS by intraperitoneal injection of neutral red (NR) dye was developed. However, it remained unknown whether NR can be used to label demyelinated lesions in PNS. In this study, we generated LPC-induced demyelination in sciatic nerve of mice, and demonstrated that the demyelinated lesions at the site of LPC injection were readily detectable at 7 days postlesion (dpl) by macroscopic observation of NR labeling. Moreover, NR staining gradually decreased from 7 to 21 dpl over the course of remyelination. Electron microscopy analysis of NR-labeled sciatic nerves at 7 dpl confirmed demyelination and myelin debris in lesions. Furthermore, fluorescence microscopy showed NR co-labeling with activated macrophages and Schwann cells in the PNS lesions. Together, NR labeling is a straightforward method that allows the macroscopic detection of demyelinated lesions in sciatic nerves after LPC injection.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Calcium-Binding Proteins; Coloring Agents; Demyelinating Diseases; Lysosomal-Associated Membrane Protein 2; Lysosomes; Macrophage Activation; Male; Mice, Inbred C57BL; Microfilament Proteins; Neutral Red; Receptors, Cell Surface; Schwann Cells; Sciatic Nerve; Mice
PubMed: 34413421
DOI: 10.1038/s41598-021-96395-4 -
Experimental Neurology Sep 2016The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by... (Review)
Review
The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by modulating the immune system to reduce the number and rate of lesion formation but are only partially effective since they are not able to restore lost myelin. In the healthy CNS, myelin continues to be generated throughout life and spontaneous remyelination occurs readily in response to insults. In patients with MS, however, remyelination eventually fails, at least in part as a result of a failure of oligodendrocyte precursor cell (OPC) differentiation and the subsequent production of new myelin. A better understanding of the molecular mechanisms and signaling pathways that drive the process of myelin sheath formation is therefore important in order to speed the development of novel therapeutics designed to target remyelination. Here we review data supporting critical roles for three highly conserved intracellular signaling pathways: Wnt/β-catenin, PI3K/AKT/mTOR, and ERK/MAPK in the regulation of OPC differentiation and myelination both during development and in remyelination. Potential points of crosstalk between the three pathways and important areas for future research are also discussed.
Topics: Animals; Cell Differentiation; Central Nervous System; Demyelinating Diseases; Humans; Myelin Sheath; Nerve Regeneration; Oligodendroglia; Signal Transduction
PubMed: 26957369
DOI: 10.1016/j.expneurol.2016.03.008 -
Proceedings of the National Academy of... Dec 2018Endogenous remyelination of the CNS can be robust and restore function, yet in multiple sclerosis it becomes less complete with time. Promoting remyelination is a major...
Endogenous remyelination of the CNS can be robust and restore function, yet in multiple sclerosis it becomes less complete with time. Promoting remyelination is a major therapeutic goal, both to restore function and to protect axons from degeneration. Remyelination is thought to depend on oligodendrocyte progenitor cells, giving rise to nascent remyelinating oligodendrocytes. Surviving, mature oligodendrocytes are largely regarded as being uninvolved. We have examined this question using two large animal models. In the first model, there is extensive demyelination and remyelination of the CNS, yet oligodendrocytes survive, and in recovered animals there is a mix of remyelinated axons interspersed between mature, thick myelin sheaths. Using 2D and 3D light and electron microscopy, we show that many oligodendrocytes are connected to mature and remyelinated myelin sheaths, which we conclude are cells that have reextended processes to contact demyelinated axons while maintaining mature myelin internodes. In the second model in vitamin B-deficient nonhuman primates, we demonstrate that surviving mature oligodendrocytes extend processes and ensheath demyelinated axons. These data indicate that mature oligodendrocytes can participate in remyelination.
Topics: Animals; Axons; Cats; Cell Differentiation; Demyelinating Diseases; Disease Models, Animal; Macaca mulatta; Microscopy, Electron, Transmission; Multiple Sclerosis; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; Remyelination
PubMed: 30487224
DOI: 10.1073/pnas.1808064115 -
Regulation of oligodendrocyte precursor migration during development, in adulthood and in pathology.Cellular and Molecular Life Sciences :... Nov 2013Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). These cells originate from oligodendrocyte precursor cells (OPCs) during development,... (Review)
Review
Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). These cells originate from oligodendrocyte precursor cells (OPCs) during development, and they migrate extensively from oligodendrogliogenic niches along the neural tube to colonise the entire CNS. Like many other such events, this migratory process is precisely regulated by a battery of positional and signalling cues that act via their corresponding receptors and that are expressed dynamically by OPCs. Here, we will review the cellular and molecular basis of this important event during embryonic and postnatal development, and we will discuss the relevance of the substantial number of OPCs existing in the adult CNS. Similarly, we will consider the behaviour of OPCs in normal and pathological conditions, especially in animal models of demyelination and of the demyelinating disease, multiple sclerosis. The spontaneous remyelination observed after damage in demyelinating pathologies has a limited effect. Understanding the cellular and molecular mechanisms underlying the biology of OPCs, particularly adult OPCs, should help in the design of neuroregenerative strategies to combat multiple sclerosis and other demyelinating diseases.
Topics: Animals; Cell Movement; Central Nervous System; Demyelinating Diseases; Humans; Multiple Sclerosis; Myelin Sheath; Neurogenesis; Neurons; Oligodendroglia
PubMed: 23689590
DOI: 10.1007/s00018-013-1365-6 -
The Journal of International Medical... Nov 2020To investigate the clinical manifestations and imaging features of older patients with white matter demyelination diagnosed by magnetic resonance imaging (MRI).
OBJECTIVE
To investigate the clinical manifestations and imaging features of older patients with white matter demyelination diagnosed by magnetic resonance imaging (MRI).
METHODS
Ninety-six patients with leukoaraiosis diagnosed by MRI were divided by their clinical diagnoses into a demyelinating group (40 cases) and a non-demyelinating group (56 cases). The imaging and clinical features of the patients in the two groups were analyzed.
RESULTS
Compared with the non-demyelinating group, there were significantly more women in the demyelinating group than men. There was no significant difference in age between the two groups. Of the 37 cases who had an imaging report of "white matter demyelination and multiple sclerosis," 36 cases had a clinical diagnosis in accordance with white matter demyelination (97.3%). Of the 59 cases who had an imaging report of "white matter demyelination", only four cases had a clinical diagnosis in accordance with demyelination (6.8%).
CONCLUSION
In older patients with headaches, vertigo, other head symptoms, and unilateral numbness as the chief complaints, a clinical diagnosis of demyelinating disease is very unlikely when the imaging report states white matter demyelination only.
Topics: Aged; Demyelinating Diseases; Female; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; White Matter
PubMed: 33148077
DOI: 10.1177/0300060520966806 -
Cell Reports May 2024Cognitive dysfunction is a feature in multiple sclerosis (MS), a chronic inflammatory demyelinating disorder. A notable aspect of MS brains is hippocampal demyelination,...
Cognitive dysfunction is a feature in multiple sclerosis (MS), a chronic inflammatory demyelinating disorder. A notable aspect of MS brains is hippocampal demyelination, which is closely associated with cognitive decline. However, the mechanisms underlying this phenomenon remain unclear. Chitinase-3-like (CHI3L1), secreted by activated astrocytes, has been identified as a biomarker for MS progression. Our study investigates CHI3L1's function within the demyelinating hippocampus and demonstrates a correlation between CHI3L1 expression and cognitive impairment in patients with MS. Activated astrocytes release CHI3L1 in reaction to induced demyelination, which adversely affects the proliferation and differentiation of neural stem cells and impairs dendritic growth, complexity, and spine formation in neurons. Our findings indicate that the astrocytic deletion of CHI3L1 can mitigate neurogenic deficits and cognitive dysfunction. We showed that CHI3L1 interacts with CRTH2/receptor for advanced glycation end (RAGE) by attenuating β-catenin signaling. The reactivation of β-catenin signaling can revitalize neurogenesis, which holds promise for therapy of inflammatory demyelination.
Topics: Chitinase-3-Like Protein 1; Neurogenesis; Hippocampus; Animals; Astrocytes; Signal Transduction; Humans; Mice; Cognition; Demyelinating Diseases; Male; Mice, Inbred C57BL; Neural Stem Cells; Cognitive Dysfunction; Receptor for Advanced Glycation End Products; Female; Multiple Sclerosis; beta Catenin; Cell Proliferation; Cell Differentiation
PubMed: 38733586
DOI: 10.1016/j.celrep.2024.114226 -
Scientific Reports May 2021The aim of this study was to investigate the mechanisms underlying demyelination and remyelination with 7.0 T multiparameter magnetic resonance imaging (MRI) in an...
The aim of this study was to investigate the mechanisms underlying demyelination and remyelination with 7.0 T multiparameter magnetic resonance imaging (MRI) in an alternative cuprizone (CPZ) mouse model of multiple sclerosis (MS). Sixty mice were divided into six groups (n = 10, each), and these groups were imaged with 7.0 T multiparameter MRI and treated with an alternative CPZ administration schedule. T-weighted imaging (TWI), susceptibility-weighted imaging (SWI), and diffusion tensor imaging (DTI) were used to compare the splenium of the corpus callosum (sCC) among the groups. Prussian blue and Luxol fast blue staining were performed to assess pathology. The correlations of the mean grayscale value (mGSV) of the pathology results and the MRI metrics were analyzed to evaluate the multiparameter MRI results. One-way ANOVA and post hoc comparison showed that the normalized TWI (T-nor), fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were significantly different among the six groups, while the mean phase (Φ) value of SWI was not significantly different among the groups. Correlation analysis showed that the correlation between the T-nor and mGSV was higher than that among the other values. The correlations among the FA, RD, MD, and mGSV remained instructive. In conclusion, ultrahigh-field multiparameter MRI can reflect the pathological changes associated with and the underlying mechanisms of demyelination and remyelination in MS after the successful establishment of an acute CPZ-induced model.
Topics: Animals; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Magnetic Resonance Imaging; Male; Mice; Multiple Sclerosis; Myelin Sheath; Remyelination
PubMed: 34040141
DOI: 10.1038/s41598-021-90597-6 -
The Journal of Neuroscience : the... Mar 2021The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs)...
The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of γ () in adult NG2 OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain. The failure of remyelination in multiple sclerosis contributes to neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following demyelination. Heparan sulfate is a highly structured sulfated carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic interferon-γ can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease.
Topics: Animals; Cell Differentiation; Cell Proliferation; Demyelinating Autoimmune Diseases, CNS; Demyelinating Diseases; Heparan Sulfate Proteoglycans; Humans; Inflammation; Interferon-gamma; Mice; Mice, Knockout; Oligodendrocyte Precursor Cells
PubMed: 33472827
DOI: 10.1523/JNEUROSCI.0580-20.2021