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 la...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.展开更多
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 decellularize...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.展开更多
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 rosmarin...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.展开更多
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 s...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.展开更多
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 isc...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 Neuro-biological 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 "Neiguan"(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 group.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.展开更多
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 oligodend...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.展开更多
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 ethid...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.展开更多
The role of the neuronal compartment in multiple sclerosis:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease affecting the central nervous system(CNS).It is usually characterized by initial relapse...The role of the neuronal compartment in multiple sclerosis:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease affecting the central nervous system(CNS).It is usually characterized by initial relapses and remissions with subsequent progressive neurological deterioration.MS is the most common acquired neurological disorder affecting展开更多
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 developm...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.展开更多
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 u...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.展开更多
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 ...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.展开更多
The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelin...The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid(SA) is mainly derived from star anise, and is reported to have antiinfluenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis(EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination.Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated m TOR. Taken together, our resultsdemonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.展开更多
The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remye...The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs,we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds.One of the most effective drugs was pinocembrin,which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival.Based on these in vitro effects,we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases.We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis(EAE)and enhanced the repair of demyelination in lysolectin-induced lesions.Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin(mTOR).Taken together,our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway,and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.展开更多
The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well establish...The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.展开更多
Insufficient remyelination due to impaired oligodendrocyte precursor cell(OPC)differentiation and maturation is strongly associated with irreversible white matter injury(WMI)and neurological deficits.We analyzed whole...Insufficient remyelination due to impaired oligodendrocyte precursor cell(OPC)differentiation and maturation is strongly associated with irreversible white matter injury(WMI)and neurological deficits.We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2(LCN2)in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1(EGR1)as the key signals contributing to LCN2-mediated insufficient OPC remyelination.In LCN-knockdown and OPC EGR1 conditional-knockout mice,we discovered enhanced OPC differentiation in developing and injured white matter(WM);consistent with this,the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical,acute WMI due to subarachnoid hemorrhage and typical,chronic WMI due to multiple sclerosis.This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.展开更多
Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyel...Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.展开更多
Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord ...Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury. In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3 K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3 K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3 K/AKT/mTOR pathway.展开更多
The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain.In many cases,the microenvironment surrounding demyelination lesions contains inhibitory ...The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain.In many cases,the microenvironment surrounding demyelination lesions contains inhibitory molecules,which lead to repair failure.Accordingly,blocking the activity of these inhibitory factors in the extracellular matrix should lead to more successful remyelination.In the central nervous system,oligodendrocytes form the myelin sheath.We performed primary cell culture and found that a natural increase in fibronectin promoted the proliferation of oligodendrocyte progenitors during the initial stage of remyelination while inhibiting oligodendrocyte differentiation.Poly-L-ornithine blocked these inhibitory effects without compromising fibronectin’s pro-proliferation function.Experiments showed that poly-L-ornithine activated the Erk1/2 signaling pathway that is necessary in the early stages of differentiation,as well as PI3K signaling pathways that are needed in the mid-late stages.When poly-L-ornithine was tested in a lysolecithin-induced animal model of focal demyelination,it enhanced myelin regeneration and promoted motor function recovery.These findings suggest that poly-L-ornithine has the potential to be a treatment option for clinical myelin sheath injury.展开更多
Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is wide...Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is widely distributed in the develo ping and adult central nervous system,participates in neural regeneration remains poorly unde rstood.In this study,we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral co rtex and striatum.Starting on day 7 after injury,CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days.Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting co rticospinal tra ct fibers in rats with cerebral ischemia,increased the expression of vesicular glutamate transporter 1 and growth-related protein 43,marke rs of the denervated spinal cord synapses,and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum.In addition,CXCR7 antibody increased the expression of CXCR4 in the striatum,increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway,and im proved rat motor function.These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration,synaptogenesis,and myelin regeneration,which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.展开更多
As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further suppo...As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further supportive functions myelin provides to axons, as seen in demyelinating diseases such as multiple sclerosis(MS), leads to neurodegeneration and results in progressive disabilities. Multiple lines of evidence have demonstrated the increasing inability of oligodendrocyte precursor cells(OPCs) to replace lost oligodendrocytes(OLs) in order to restore lost myelin. Much research has been dedicated to reveal potential reasons for this regeneration deficit but despite promising approaches no remyelination-promoting drugs have successfully been developed yet. In addition to OPCs neural stem cells of the adult central nervous system also hold a high potential to generate myelinating OLs. There are at least two neural stem cell niches in the brain, the subventricular zone lining the lateral ventricles and the subgranular zone of the dentate gyrus, and an additional source of neural stem cells has been located in the central canal of the spinal cord. While a substantial body of literature has described their neurogenic capacity, still little is known about the oligodendrogenic potential of these cells, even if some animal studies have provided proof of their contribution to remyelination. In this review, we summarize and discuss these studies, taking into account the different niches, the heterogeneity within and between stem cell niches and present current strategies of how to promote stem cell-mediated myelin repair.展开更多
文摘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.
基金supported by grants from the National Key R&D Program of China,No.2017YFA0104704(to BQL)the Young Elite Scientist Sponsorship Program(YESS)by China Association for Science and Technology(CAST),No.2018QNRC001(to BQL)+1 种基金the Fundamental Research Funds for the Central Universities,China,No.18ykpy38(to BQL)the National Natural Science Foundation of China,Nos.81971157(to BQL),81891003(to YSZ).
文摘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.
基金supported by the Natural Science Foundation of Jiangsu Province of China,No.BK20171180(to XRW)
文摘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.
基金partially supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health(R21 NS098170, to JC and CBS)Kentucky Spinal Cord and Head Injury Research Trust(16-3 A, to JC and CBS)the National Natural Science Foundation of China(81601957, to YW)。
文摘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.
文摘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 Neuro-biological 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 "Neiguan"(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 group.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.
基金supported by National Multiple Sclerosis Society,NIH and the Guthy-Jackson Charitable Foundation
文摘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.
文摘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.
文摘The role of the neuronal compartment in multiple sclerosis:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease affecting the central nervous system(CNS).It is usually characterized by initial relapses and remissions with subsequent progressive neurological deterioration.MS is the most common acquired neurological disorder affecting
文摘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.
文摘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.
基金We would like to thank the Core Facilities,Zhejiang University School of Medicine for technical support.This work was supported by the National Natural Science Foundation of China(81973302,81903580)the National Key R&D Program of China(2020YFA0803900)the Zhejiang Provincial Natural Science Foundation of China(LR17H310001,LYY22H310003).
文摘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.
基金supported by the National Natural Science Foundation of China(31571066 and 31771129)the National Basic Research Development Program of China(2016YFA0100802)
文摘The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid(SA) is mainly derived from star anise, and is reported to have antiinfluenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis(EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination.Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated m TOR. Taken together, our resultsdemonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.
基金This work was supported by the National Natural Science Foundation of China(31771129).
文摘The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs,we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds.One of the most effective drugs was pinocembrin,which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival.Based on these in vitro effects,we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases.We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis(EAE)and enhanced the repair of demyelination in lysolectin-induced lesions.Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin(mTOR).Taken together,our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway,and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.
基金supported by the National Natural Science Foundation of China(81771337 and 81271345)the National Key R&D Program of China(2017YFA0104202)+2 种基金the Natural Science Foundation of Jiangsu Province(BK20161174)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(18KJB180028)the Six Talent Peaks Project in Jiangsu Province(2015 to RY)。
文摘The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system(CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells(OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone(CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type(WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3 b, a key regulatory kinase in the Wnt pathway, regulates the ability of b-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763,a selective inhibitor of GSK-3 b activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3 b, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.
基金This work was supported by the National Natural Science Foundation of China(81901216 and 82030036)Southwest Hospital(SWH2018BJKJ-05 and SWH2015QN13)the Chongqing Talent Program(4139Z2391).
文摘Insufficient remyelination due to impaired oligodendrocyte precursor cell(OPC)differentiation and maturation is strongly associated with irreversible white matter injury(WMI)and neurological deficits.We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2(LCN2)in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1(EGR1)as the key signals contributing to LCN2-mediated insufficient OPC remyelination.In LCN-knockdown and OPC EGR1 conditional-knockout mice,we discovered enhanced OPC differentiation in developing and injured white matter(WM);consistent with this,the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical,acute WMI due to subarachnoid hemorrhage and typical,chronic WMI due to multiple sclerosis.This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.
基金supported by the National Natural Science Foundation of China,Nos.82001282(to PW)and 81960232(to PW)Overseas Students’Innovation and Entrepreneurship Individual Project of Ningxia(2021)(to PW)+1 种基金Youth Talents Supporting Program of Ningxia Medical University and Ningxia,Nos.XT2019018(to PW),TJGC2019081(to PW)College Students’Innovation and En trepreneurship Training Program,No.X202210752038(to FYY)。
文摘Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.
基金supported by the National Key R&D Program of China,No.2020YFC2008502 (to QW)the National Natural Science Foundation of China,No. 82172534 (to QW)。
文摘Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury. In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3 K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3 K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3 K/AKT/mTOR pathway.
基金supported by the National Nature Science Foundation of China,Nos.81371338(to HF)and 82071369(PPY)。
文摘The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain.In many cases,the microenvironment surrounding demyelination lesions contains inhibitory molecules,which lead to repair failure.Accordingly,blocking the activity of these inhibitory factors in the extracellular matrix should lead to more successful remyelination.In the central nervous system,oligodendrocytes form the myelin sheath.We performed primary cell culture and found that a natural increase in fibronectin promoted the proliferation of oligodendrocyte progenitors during the initial stage of remyelination while inhibiting oligodendrocyte differentiation.Poly-L-ornithine blocked these inhibitory effects without compromising fibronectin’s pro-proliferation function.Experiments showed that poly-L-ornithine activated the Erk1/2 signaling pathway that is necessary in the early stages of differentiation,as well as PI3K signaling pathways that are needed in the mid-late stages.When poly-L-ornithine was tested in a lysolecithin-induced animal model of focal demyelination,it enhanced myelin regeneration and promoted motor function recovery.These findings suggest that poly-L-ornithine has the potential to be a treatment option for clinical myelin sheath injury.
基金supported by the National Natural Science Foundation of China,Nos.81401002 (to SSZ),81801 053 (to XQZ)。
文摘Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is widely distributed in the develo ping and adult central nervous system,participates in neural regeneration remains poorly unde rstood.In this study,we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral co rtex and striatum.Starting on day 7 after injury,CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days.Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting co rticospinal tra ct fibers in rats with cerebral ischemia,increased the expression of vesicular glutamate transporter 1 and growth-related protein 43,marke rs of the denervated spinal cord synapses,and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum.In addition,CXCR7 antibody increased the expression of CXCR4 in the striatum,increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway,and im proved rat motor function.These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration,synaptogenesis,and myelin regeneration,which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.
基金The German Academic Exchange Service (DAAD) supported RAsupported by grants to PK by the German Research Council (DFG+3 种基金 SPP1757/KU1934/2_1, KU1934/5-1)the Christiane and Claudia Hempel Foundation for clinical stem cell research and Young Gliasupported in part by the Walter and Ilse Rose Foundationthe James and Elisabeth Cloppenburg, Peek & Cloppenburg Düsseldorf Foundation
文摘As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further supportive functions myelin provides to axons, as seen in demyelinating diseases such as multiple sclerosis(MS), leads to neurodegeneration and results in progressive disabilities. Multiple lines of evidence have demonstrated the increasing inability of oligodendrocyte precursor cells(OPCs) to replace lost oligodendrocytes(OLs) in order to restore lost myelin. Much research has been dedicated to reveal potential reasons for this regeneration deficit but despite promising approaches no remyelination-promoting drugs have successfully been developed yet. In addition to OPCs neural stem cells of the adult central nervous system also hold a high potential to generate myelinating OLs. There are at least two neural stem cell niches in the brain, the subventricular zone lining the lateral ventricles and the subgranular zone of the dentate gyrus, and an additional source of neural stem cells has been located in the central canal of the spinal cord. While a substantial body of literature has described their neurogenic capacity, still little is known about the oligodendrogenic potential of these cells, even if some animal studies have provided proof of their contribution to remyelination. In this review, we summarize and discuss these studies, taking into account the different niches, the heterogeneity within and between stem cell niches and present current strategies of how to promote stem cell-mediated myelin repair.
