The contribution of oligodendrocytes and oligodendrocyte progenitor cells to central nervous system repair in multiple sclerosis： perspectives for remyelination therapeutic strategies

Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells（OPCs） and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.

Decellularized optic nerve functional scaffold transplant facilitates directional axon regeneration and remyelination in the injured white matter of the rat spinal cord

Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury.However,achieving good outcome remains difficult.Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites.However,it has not been reported whether this material promotes axonal regeneration in vivo.In the present study,a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells.This functional scaffold promoted the directional growth and remyelination of regenerating axons.In vitro,the porcine decellularized optic nerve contained many straight,longitudinal channels with a uniform distribution,and microscopic pores were present in the channel wall.The spatial micro topological structure and extracellular matrix were conducive to the adhesion,survival and migration of neural stem cells.The scaffold promoted the directional growth of dorsal root ganglion neurites,and showed strong potential for myelin regeneration.Furthermore,we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo.Four weeks later,the regenerating axons grew straight,the myelin sheath in the injured/transplanted area recovered its structure,and simultaneously,the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced.Together,these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration.All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University(approval No.SYSU-IACUC-2019-B034)on February 28,2019.

Rosmarinic acid ameliorates hypoxia/ischemia induced cognitive deficits and promotes remyelination

Rosmarinic acid,a common ester extracted from Rosemary,Perilla frutescens,and Salvia miltiorrhiza Bunge,has been shown to have protective effects against various diseases.This is an investigation into whether rosmarinic acid can also affect the changes of white matter fibers and cognitive deficits caused by hypoxic injury.The right common carotid artery of 3-day-old rats was ligated for 2 hours.The rats were then prewarmed in a plastic container with holes in the lid,which was placed in 37°C water bath for 30 minutes.Afterwards,the rats were exposed to an atmosphere with 8% O2 and 92% N2 for 30 minutes to establish the perinatal hypoxia/ischemia injury models.The rat models were intraperitoneally injected with rosmarinic acid 20 mg/kg for 5 consecutive days.At 22 days after birth,rosmarinic acid was found to improve motor,anxiety,learning and spatial memory impairments induced by hypoxia/ischemia injury.Furthermore,rosmarinic acid promoted the proliferation of oligodendrocyte progenitor cells in the subventricular zone.After hypoxia/ischemia injury,rosmarinic acid reversed to some extent the downregulation of myelin basic protein and the loss of myelin sheath in the corpus callosum of white matter structure.Rosmarinic acid partially slowed down the expression of oligodendrocyte marker Olig2 and myelin basic protein and the increase of oligodendrocyte apoptosis marker inhibitors of DNA binding 2.These data indicate that rosmarinic acid ameliorated the cognitive dysfunction after perinatal hypoxia/ischemia injury by improving remyelination in corpus callosum.This study was approved by the Animal Experimental Ethics Committee of Xuzhou Medical University,China (approval No.20161636721) on September 16,2017.

The mechanism of Naringin-enhanced remyelination after spinal cord injury

Our previous study revealed that intragastric administration of naringin improved remyelination in rats with spinal cord injury and promoted the recovery of neurological function of the injured spinal cord.This study sought to reveal the mechanisms by which naringin improves oligodendrocyte precursor cell differentiation and maturation,and promotes remyelination.Spinal cord injury was induced in rats by the weight-drop method.Naringin was intragastrically administered daily（20,40 mg/kg） for 4 weeks after spinal cord injury induction.Behavioral assessment,histopathological staining,immunofluorescence spectroscopy,ultrastructural analysis and biochemical assays were employed.Naringin treatment remarkably mitigated demyelination in the white matter,increased the quality of myelinated nerve fibers and myelin sheath thickness,promoted oligodendrocyte precursor cell differentiation by upregulating the expression of NKx2.2 and 2′3′-cyclic nucleotide 3′-phosphodiesterase,and inhibited β-catenin expression and glycogen synthase kinase-3β（GSK-3β） phosphorylation.These findings indicate that naringin treatment regulates oligodendrocyte precursor cell differentiation and promotes remyelination after spinal cord injury through the β-catenin/GSK-3β signaling pathway.

Dynamic glial response and crosstalk in demyelination-remyelination and neurodegeneration processes

Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple sclerosis, followed by the entry of immune cells and activation of local microglia and astrocytes.Glial cells(microglia, astrocytes, and oligodendrocyte lineage cells) are known as the important mediators of neuroinflammation, all of which play major roles in the pathogenesis of multiple sclerosis.Network communications between glial cells affect the activities of oligodendrocyte lineage cells and influence the demyelination-remyelination process.A finely balanced glial response may create a favorable lesion environment for efficient remyelination and neuroregeneration.This review focuses on glial response and neurodegeneration based on the findings from multiple sclerosis and major rodent demyelination models.In particular, glial interaction and molecular crosstalk are discussed to provide insights into the potential cell-and molecule-specific therapeutic targets to improve remyelination and neuroregeneration.

Acupuncture effects on serum myelin basic protein and remyelination following 30 minutes and 2 hours of ischemia in a rat model of cerebral ischemia-reperfusion injury

BACKGROUND： Acupuncture treatment on injured cerebral axons has shown to provide efficacy in clinical practice. It is unknown whether acupuncture produces therapeutic effects by protecting injured cerebral myelin in ischemic stroke. OBJECTIVE： To test whether acupuncture provides protection for injured cerebral myelin, based on quantitative data from cerebral ischemia-reperfusion rats, and to compare the effects of early and late acupuncture on serum myelin basic protein （MBP） content and remyelination of the ischemic internal capsule.DESIGN, TIME AND SETTING： A randomized, controlled experiment was performed at the Neurobiological Laboratory, Sichuan University from March 2005 to March 2006. MATERIALS： ＂Hua Tuo＂ Brand filiform needles were produced by the Medical Instrument Factory of Suzhou, China.METHODS： A total of 52 adult, healthy, male, Sprague Dawley rats were randomly assigned to four groups： control （n = 4）, model （n = 16）, early acupuncture （n = 16）, and late acupuncture （n = 16）. The focal cerebral ischemia-reperfusion model was established by middle cerebral artery occlusion in the right hemisphere using the modified thread embolism method in the latter three groups. Early and late acupuncture groups underwent acupuncture after ischemia for 30 minutes and 2 hours using the Xingnaokaiqiao needling method, respectively. Acupoints were ＂Neiguarf＇ （PC 6） and ＂Sanyinjiao＂ （SP 6） on the bilateral sides, as well as ＂Shuigou＇ （DU 26） and ＂Baihui＂ （DU 20） with stimulation for 1 minute at each acupoint. Acupuncture at all acupoints was performed two or three times while the needle was retained, once per day. No special handling was administered to the control clroup.MAIN OUTCOME MEASURES： For each group, remyelination of the internal capsule was observed by Pal-Weigert＇s myelin staining and serum MBP content was detected using enzyme-linked immunosorbent assay method on days 1,3, 5, and 7 following ischemia-reperfusion injury.RESULTS： Compared with the control group, massive demyelination of the internal capsule occurred, and serum MBP content increased in the model group （P 〈 0.05）. Compared with the model group, the extent of demyelination in the internal capsule was less distinct and serum MBP content was significantly less in the early and late acupuncture group （P 〈 0.01 ）. Compared with the late acupuncture group, serum MBP content reached a peak later and the peak value was less in the early acupuncture group. CONCLUSION： Results suggest that acupuncture exerts a protective effect on injured cerebral myelin in ischemia-reperfusion rats by reducing serum MBP content and promoting remyelination. The study also suggests that the effect of early acupuncture is superior to late acupuncture.

Effect of glial cells on remyelination after spinal cord injury

Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

Effect of adenovirus-mediated gene transfer of Olig1 on oligodendrocyte differentiation and remyelination in a rat model of focal cerebral ischemia

BACKGROUND： The transcription factor Oligl is required for oligodendrocyte maturation and demyelinated lesion repair, and is a key regulator of myelinogenesis following ischemia. OBJECTIVE： To examine the efficacy of intraventricular injection of a recombinant adenovirus-expressing Oligl gene （Ad5-Oligl-eGFP） on oligodendrocyte maturation and myelin repair following focal cerebral ischemia. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Department of Neurology, Beijing Friendship Hospital Affiliated to Capital Medical University from January 2007 to March 2008. MATERIALS： Adenovirus and a recombinant adenovirus containing Oiigl gene （Ad5-Oligl） were provided by Vector Gene Technology, China. METHODS： All 50 rats were induced by middle cerebral artery occlusion. A total of 46 rats were successfully induced and were subsequently randomly assigned to a adenovirus （Ad5） group and recombinant adenovirus-expression Oligl gene （Ad5-Oligl） group, with 23 rats per group. One day after middle cerebral artery occlusion, either Ad5-Oligl-eGFP or Ad5-eGFP （10 μL, 2.3 ×10^11/mL） was injected into the lateral ventricle on the ischemic hemisphere. MAIN OUTCOME MEASURES： Adenovirus-mediated Oligl gene expression in vitro and in vivo was measured by reverse transcription-polymerase chain reaction and immunofluorescence, respectively. Myelin basic protein （MBP） levels were evaluated by Western Blot, immunostaining, and electron microscopy. RESULTS： Exogenous Oligl expression was measured at the periventricular zone of the lateral ventricle 1 day after Ad5-Oligl injection. In the Ad5-Oligl-treated group, MBP protein levels and average intensity of MBP-immunoreactivity （-ir） increased 28 days after middle cerebral artery occlusion, compared with the control group （P 〈 0.01, P 〈 0.05）. Furthermore, myelinated axonal numbers markedly increased following Ad5-Oligl treatment. CONCLUSION： The present data suggested that Ad5-Oligl gene therapy increased MBP expression and the number of remyelinating axons following cerebral ischemia.

Gas6-Tyro3 signaling is required for Schwann cell myelination and possible remyelination

Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent studies have demonstrated that myelination is regulated by the TYRO3,AXL（also known as UFO）and MERTK.

Electrical stimulation of cortical neurons promotes oligodendrocyte development and remyelination in the injured spinal cord

Background and early studies： Endogenous tri-potential neural stem cells （NSCs） exist in the adult mammalian central nervous system （CNS）. In the spinal cord, NSCs distribute throughout the entire cord, but exist predominately in white matter tracts. The phenotypic fate of these cells in white matter is glial, largely oligodendrocyte, but not neuronal.

Research advancements of axonal remyelination in spinal cord injury

Spinal cord injuries(SCI)usually result in impairment of axonal conduction and sensorimotor function.There are no effective therapy to completely repair SCI.Axonal demyelination is very common as a pathologic change in SCI,and demyelination partly contributes to neural function impairment.So,it may be reasonable that remyelination of demyelinated axons become one of effective therapeutic targets for SCI treatment. Demyelination involves myelin breakdown and loss of myelin-forming cells(oligodendrocytes).The death of oligodendrocytes plays a key role in axonal demyelination in SCI.Recently a number of studies demonstrate that cell replacements could facilitate axonal remyelination and restore axonal conductive func- tion.Thus,it is expected that myelinogenetic cell transplantation(oligodendroglial lineage)will have good prospect as an effective therapy to improve axonal remyelination and restore neural function for SCI treat- ment in the near future.

New ex vivo demyelination/remyelination models to defeat multiple sclerosis and neuromyelitis optica

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory diseases of the central nervous system (CNS) resulting in CNS inflammation, infiltration of peripheral immune cells, loss of myelin and oligodendrocytes, interruption of axonal communication, and neurologic deficits. Following oligodendrocyte injury, newly generated myelinating oligodendrocytes derived from oligodendrocyte progenitors (OPCs) may produce new myelin sheaths around denuded axons (remyelination) restoring neuronal function (Verden and Macklin, 2016). While remyelination is apparent in MS lesions, the process is often inefficient;in NMO, remyelination is even more limited.

Zebrafish model for assessing remyelination

This study was aimed to assess remyelination and axon regeneration of compounds using Hunter Biotech＇ s zebrafish MS models. Zebrafish at 2 day post fertilization （2 dpf） were treated with demyelinating agent ethidium bromide （EB） for 72 hours （hrs） to induce demyelination. After removing EB, demyelinated zebrafish were treated with test compounds for another 24 hrs; Compound effect on demyelination-associated motility was as- sessed using a video-track motion detector. We found that compounds 2 and 9 recovered motility in EB-induced de- myelinated zebrafish ; whereas compounds 2 and 9 had significant effect on motility. Compounds 2 and 9 were con- firmed by whole mount anti-myelin basic protein （anti-MBP） immunostainging, further supporting that demyelina- tion-associated motility assay （primary assay） in combination with Fluoro Myelin staining （secondary assay） is a reliable array of methods for relatively high throughput in vivo remyelinating drug screening and assessment.

The choline pathway as a strategy to promote central nervous system(CNS) remyelination

Multiple sclerosis is a chronic companied by demyelination inflammatory disease that is ac- and axonal damage resulting in neurological deficits. Remyelination is the natural endogenous repair mechanism of demyelinated axons and it is supposed to protect axons/neurons from degeneration and thus the patient from progressive disability （Franklin and Ffrench-Constant, 2008）. Current therapeutics for patients with multiple sclerosis are to some extent very effective in inhibiting neuroinflamma- tion and demyelination. However, to date there are no substanc- es available that can enhance remyelination. Remyelination is the result of recruitment/proliferation of new oligodendrocyte precursor cells （OPC） and differentiation into mature myelin producing oligodendrocytes （Franklin and Ffrench-Constant, 2008）. These processes are supported by many factors and signals and failure at any stage might lead to repair failure. Strategies to enhance myelin repair are either the promotion of endogenous repair mechanisms via modulation of OPC prolif- eration and oligodendrocyte differentiation or the transplantion of myelinating cells into lesions. Due to the multiloculated pro- cess in multiple sclerosis and the ethical problems with the cell source, the latter is less favoured. The endogenous promotion of remvelination could be achieved by several approaches such as：

Targeting remyelination treatment for multiple sclerosis

Since disability in multiple sclerosis(MS) is a product of neurodegeneration and deficient remyelination, the ability to enhance neuroregeneration and myelin regeneration in MS is an enticing goal for MS drug development. In particular, remyelination treatments could promote return of neurological function and also prevent further axonal loss and neurodegeneration in MS due to trophic effects of myelin. The study of remyelination has advanced dramatically in the last several years such that a number of pathways inhibiting remyelination have been discovered, including those involving LINGO-1, Notch-1, hyaluronan, retinoid X receptor, and wnt/?-catenin. Other approaches such as high throughput drug screening for remyelination drugs have caught fire, with identification of dozens of known drugs with oligodendrocyte maturation stimulatory effects. Several drugs identified through screens and other mechanisms are in the process of being further evaluated for remyelination in MS and MS models. We discuss the potential molecular targets and the variety of mechanisms towards drug identification and development in remyelination for MS.

S4B-5 Effect of Fasudil on Remyelination Following the Cuprizone-Induced Demyelination in Male C57BL/6 Mice

Background Multiple sclerosis(MS)is an autoimmune,inflammatory demyelinating disease of the central nervous system(CNS)characterized by de-/remyelination,neuroinflammation and oligodendrocyte loss.Although a greater understanding of MS have increased acquaintance of the pathogenesis and pathophysiology,the exploration of treatment is still challenging.Fasudil,one of the most thoroughly studied Rho kinase(ROCK)inhibitors,has been shown to have effects in neurodegenerative diseases.However,the effect of Fasudil on preventing the progression of the demyelination in MS has not been evaluated.Cuprizone(CPZ)-induced demyelination is a model used to study de-/remyelination in the CNS.Some aspects of the histological pattern induced by CPZ are similar to MS.The aim of the study is to investigate the effect of Fasudil on CPZ-induced demyelination,and to explore the mechanisms for the possible remyelination.Materials and Methods Male C57 BL/6 mice(10-12 weeks old)were assigned into normal group,fed a normal diet;CPZ group,fed CPZ and intraperitoneally(i.p.)injected with normal saline after 4 weeks for consecutive 2 weeks;Fasudil-treated CPZ group,which were i.p.injected with Fasudil(40 mg/kg/day)after 4 weeks for consecutive 2 weeks.All groups were assessed by Elevated plus-maze(EPM)test and Pole test at the end of the experiment.For examing the extent of demyelination,Luxol Fast Blue(LFB)staining,Black GoldⅡand myelin basic protein(MBP)immunohistochemistry staining were used for slides of brains.Splenic MNCs were fixed and stained with the following antibodies:Alexa Fluor B220,FITCCD4/PE-IFN-γ,FITC-CD4/PE-IL-17.At least 10,000 events were collected using flow cytometer.Results Following CPZ-exposure,mice presented a lower density of LFB,Black GoldⅡand MBP expression,loss of mature oligodendrocytes.Spleen atrophy was observed in CPZ-group compared to normal mice,and we firstly found that CPZ feeding induced the formation of MOG antibody.Fasudil treatment improved behavioral abnormality,promoted remyelination,inhibited spleen atrophy and production of MOG antibodies,prevented the infiltration of peripheral T cells,B cells,macrophages,and declined the neuroinflammation by inhibiting Iba1+iNOS+,Iba1+NF-κB+microglia.Fasudil treatment also reduced the levels of IL-1β,IL-6 and TNF-α.Discussion In this study,we demonstrated that demyelinating model was successfully established.Then we tested whether Fasudil plays a remyelinating role in this model.Spleen atrophy was observed after CPZ-feeding compared to normal mice.Previous studies have shown that splenic atrophy in experimental stroke may contribute to brain injury possibly through the release of inflammatory mediators and spleen-derived inflammatory cells to the circulation and migration into the brain,which aggravate the brain inflammatory response and led to secondary injure.At present,we lack direct evidence to elucidate the mechanisms for spleen atrophy in CPZ-induced demyelination.We firstly found that CPZ-feeding induced the formation of MOG antibody.Recent study indicated that BBB hyperpermeability precedes demyelination in CPZ-demyelinating model.Another study suggested that debris of damaged cells in the CNS may present as antigens after penetrating the BBB,giving rise to autoantibodies.Therefore,it is possible that the myelin debris produced the destruction of myelin sheath can enter the blood circulation and stimulate the immune response of T and B cells.We found that MOG antibody was elevated in the supernatant of cultured plenocytes,indicating that the MOG antibodies were derived from peripheral immune cells.Our results showed that the level of MOG antibody in the brain homogenate of CPZ-treated mice was higher than that of normal mice,suggesting that antibodies can enter brain tissue and anti a-synuclein antibody was negative,which indicate that anti MOG antibody is a specific antibody.In our study,MOG antibody was capable of being detected in the brain of CPZ-treated mice,providing a possibility for specific MOG antibody-mediated oligodendrocyte damage.CPZ induced a wide range of Iba-1+microglia,which was inhibited by Fasudil.These results suggest that the suppression of inflammatory microenvironment may contribute to the remyelination.In conclusion,the administration of Fasudil promoted remyelination by multiple mechanisms.

MFG-E8 Alleviates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Phagocytosing Myelin Debris and Promoting Remyelination

Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter.However,milk fat globule-epidermal growth factor-factor 8(MFG-E8),a microglial phagocytosis-related protein,has not been well studied in hypoperfusion-related cognitive dysfunction.We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis(BCAS).MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests.In addition,we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy.Meanwhile,MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS.Moreover,in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via theαVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes.Interestingly,we found that MFG-E8 was mainly derived from astrocytes,not microglia.Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.

Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are available.Here,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical structure.In a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral hypoperfusion.The therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ischemia.Mechanistically,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons.Additionally,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral hypoperfusion.In summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion.It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

EZH2-dependent myelination following sciatic nerve injury

Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.

Overview of emerging therapies for demyelinating diseases

This paper provides an overview of autoimmune disorders of the central nervous system,specifically those caused by demyelination.We explore new research regarding potential therapeutic interventions,particularly those aimed at inducing remyelination.Remyelination is a detailed process,involving many cell types–oligodendrocyte precursor cells(OPCs),astrocytes,and microglia–and both the innate and adaptive immune systems.Our discussion of this process includes the differentiation potential of neural stem cells,the function of adult OPCs,and the impact of molecular mediators on myelin repair.Emerging therapies are also explored,with mechanisms of action including the induction of OPC differentiation,the transplantation of mesenchymal stem cells,and the use of molecular mediators.Further,we discuss current medical advancements in relation to many myelin-related disorders,including multiple sclerosis,optic neuritis,neuromyelitis optica spectrum disorder,myelin oligodendrocyte glycoprotein antibodyassociated disease,transverse myelitis,and acute disseminated encephalomyelitis.Beyond these emerging systemic therapies,we also introduce the dimethyl fumarate/silk fibroin nerve conduit and its potential role in the treatment of peripheral nerve injuries.Despite these aforementioned scientific advancements,this paper maintains the need for ongoing research to deepen our understanding of demyelinating diseases and advance therapeutic strategies that enhance affected patients’quality of life.