Oligodendrocytes in central nervous system diseases:the effect of cytokine regulation

Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies.

Nogo-A aggravates oxidative damage in oligodendrocytes

Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition,neuronal homeostasis,precursor migration,plasticity,and neurodegeneration,its functions in the process of oxidative injury are largely uncharacterized.In this study,oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats.We used hydrogen peroxide(H2O2)to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes.After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes,Nogo-A expression was increased,and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death.Furthermore,knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2.Intervention with a Nogo-66 antibody,a LINGO1 blocker,or Y27632,an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway,did not affect the death of oligodendrocytes.Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes.In conclusion,Nogo-A aggravated reactive oxygen species damage in oligodendrocytes,and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process.This study was approved by the Ethics Committee of Peking University People’s Hospital,China(approval No.2018PHC081)on December 18,2018.

Dysfunction of the oligodendrocytes in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disorder characterized by irreversible deterioration of upper and lower motor neurons(MNs).Previously,studies on the involvement of glial cells in the pathogenic process of ALS have mainly revolved around astrocytes and microglia.And oligodendrocytes(OLs)have only recently been highlighted.Grey matter demyelination within the motor cortex and proliferation of the oligodendrocyte precursor cells(OPCs)was observed in ALS patients.The selective ablation of mutant SOD1(the dysfunctional superoxide dismutase)from the oligodendrocyte progenitors after birth significantly delayed disease onset and prolonged the overall survival in ALS mice model(SOD1G37R).In this study,we review the several mechanisms of oligodendrocyte dysfunction involved in the pathological process of myelin damage and MNs death during ALS.Particularly,we examined the insufficient local energy supply from OLs to axons,impaired differentiation from OPCs into OLs mediated by oxidative stress damage,and inflammatory injury to the OLs.Since increasing evidence depicted that ALS is not a disease limited to MNs damage,exploring the mechanisms by which oligodendrocyte dysfunction is involved in MNs death would contribute to a more comprehensive understanding of ALS and identifying potential drug targets.

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.

Promotive Effects of Yokukansan, a Traditional Japanese Medicine, on Proliferation and Differentiation of Cultured Mouse Cortical Oligodendrocytes

Effects of yokukansan, a traditional Japanese medicine, on proliferation and differentiation of oligodendrocytes were examined using purified mouse cortical oligodendrocyte precursor cells (OPCs). OPCs were cultured for four days, and proliferation was evaluated by counting A2B5 (a specific antibody to OPC)-reactive cells on the second day of cell culture. Differentiation from OPC to oligodendrocyte was evaluated by counting O4 (a specific antibody to detect differentiated cells in various stages)-reactive cells on the fourth day of culture. The effects of yokukansan (final concentration: 100 or 200 μg/ml) on proliferation and differentiation were examined by adding it to the medium for four days. Yokukansan increased not only the number of A2B5-positive cells on the second day but also the number of O4-positive cells on the fourth day compared to those in the corresponding controls. A WST-8 assay was used to identify active components from seven components of Uncaria Hook (UH), one of the constituent galenicals of yokukansan. Geissoschizine methyl ether (GM: 0.1 - 3.0 μM) was identified by this screening assay and increased the number of A2B5-positive cells on the second day and O4-positive cells on the fourth day as yokukansan did. These results suggest that yokukansan promotes the proliferation and differentiation of oligodendrocytes, and also that GM contained in UH is one of active components responsible for this effect of yokukansan.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells.Oligodendrocytes perform essential roles in the central nervous system,including myelin sheath formation,axonal metabolism,and neuroplasticity regulation.They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation,differentiation,and apoptosis.Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes.These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways,but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function.In this review,we summarize the effects of general anesthetic agents on oligodendrocytes.We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

Superresolution live-cell imaging reveals that the localization of TMEM106B to filopodia in oligodendrocytes is compromised by the hypomyelination-related D252N mutation

Hypomyelination leukodystrophies constitute a group of heritable white matter disorders exhibiting defective myelin development.Initially identified as a lysosomal protein,the TMEM106B D252N mutant has recently been associated with hypomyelination.However,how lysosomal TMEM106B facilitates myelination and how the D252N mutation disrupts that process are poorly understood.We used superresolution Hessian structured illumination microscopy(Hessian-SIM)and spinning discconfocal structured illumination microscopy(SD-SIM)to find that the wild-type TMEM106B protein is targeted to the plasma membrane,filopodia,and lysosomes in human oligodendrocytes.The D252N mutation reduces the size of lysosomes in oligodendrocytes and compromises lysosome changes upon starvation stress.Most importantly,we detected reductions in the length and number of filopodia in cells expressing the D252N mutant.PLP1 is the most abundant myelin protein that almost entirely colocalizes with TMEM106B,and coexpressing PLP1 with the D252N mutant readily rescues the lysosome and filopodia phenotypes of cells.Therefore,interactions between TMEM106B and PLP1 on the plasma membrane are essential for filopodia formation and myelination in oligodendrocytes,which may be sustained by the delivery of these proteins from lysosomes via exocytosis.

Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content

Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons.Abnormal myelin sheath is associated with many neurological diseases.Meningioma-expressed antigen 6(Mea6)/cutaneous T cell lymphoma-associated antigen 5C(cTAGE5C)plays an important role in vesicle trafficking from the endoplasmic reticulum(ER)to Golgi,and conditional knockout(cKO)of Mea6 in the brain significantly affects neural development and brain function.However,whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear.In this study,by using different models of diffusion magnetic resonance imaging,we showed that cKO of Mea6 in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter,as well as a significant decrease of cholesterol and triglycerides in brains.Our lipidomic analysis of purified myelin sheath for the first time showed that Mea6 elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome,especially the proportion of very long chain fatty acids(VLCFAs).In particular,the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice.The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long chain fatty acids(ELOVLs).Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath,myelin lipids,and the pathogenesis of white matter diseases.

The Protective Effects of Flavonoids from Scutellaria Baicalensis Georgi Stems and Leaves on Oligodendrocyte Damage Induced by Aβ1-42

Aim: This study aimed to investigate the protective effects of flavonoids from the stem and leaves of Scutellaria baicalensis Georgi (SSFs) against Aβ1-42-induced oligodendrocytes (OL) damage. Methods: Immunofluorescence was used for the detection of myelin-associated glycoprotein (MAG), a characteristic protein of rat oligodendrocytes (OLN-93 cells). To evaluate the potential protective effects of SSFs on OLN-93 cells injured by Aβ1-42, an injury model was established by subjecting OLN-93 cells to Aβ1-42 exposed. Cell morphology was examined using an inverted microscope, while cell viability was assessed using the colorimetric method of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Additionally, lactate dehydrogenase (LDH) was measured using the pyruvic acid reduction assay. The Ginkgo biloba leaf extract (GBE) injection was used as a positive control. Results: A total of >95% of the MAG immunofluorescence-positive cells were identified as oligodendrocytes. Gradually increasing concentrations of SSFs impaired the cells, and the maximum nondetrimental dose for OLN-93 cells was 75 mg/L. This study assessed the effects of SSFs on OLN-93 cells damaged by Aβ1-42. The results indicated that SSFs significantly improved OLN-93 cell morphological abnormal changes, increased the OLN-93 cell survival rate, and reduced LDH release. Conclusion: SSFs can alleviate Aβ1-42-induced damage of OL.

Autophagy in neural stem cells and glia for brain health and diseases

Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation,maturation,and survival.Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells.Autophagy arbitrates structural and functional remodeling during the cell differentiation process.Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases.Only recently,studies have begun to shed light on autophagy regulation in glia(microglia,astrocyte,and oligodendrocyte)in the brain.Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development,synaptic function,brain metabolism,cellular debris clearing,and restoration of damaged or injured tissues.Thus,this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions,neurodevelopmental disorders,and neurodegenerative diseases.This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases.

Star power: harnessing the reactive astrocyte response to promote remyelination in multiple sclerosis

Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.

The physiological role of the unfolded protein response in the nervous system

The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfolded proteins.The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity,reducing protein biosynthesis,and promoting protein degradation.It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress.Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system.Here,we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions,and highlight the critical role of the UPR in brain development,memory storage,retinal cone development,myelination,and maintenance of myelin thickness.

Contribution of glial cells to the neuroprotective effects triggered by repetitive magnetic stimulation:a systematic review

Repetitive transcranial magnetic stimulation has been increasingly studied in different neurological diseases,and although most studies focus on its effects on neuronal cells,the contribution of nonneuronal cells to the improvement trigge red by repetitive transcranial magnetic stimulation in these diseases has been increasingly suggested.To systematically review the effects of repetitive magnetic stimulation on non-neuronal cells two online databases.Web of Science and PubMed were searched fo r the effects of high-frequency-repetitive transcranial magnetic stimulation,low-frequencyrepetitive transcranial magnetic stimulation,intermittent theta-bu rst stimulation,continuous thetaburst stimulation,or repetitive magnetic stimulation on non-neuronal cells in models of disease and in unlesioned animals or cells.A total of 52 studies were included.The protocol more frequently used was high-frequency-repetitive magnetic stimulation,and in models of disease,most studies report that high-frequency-repetitive magnetic stimulation led to a decrease in astrocyte and mic roglial reactivity,a decrease in the release of pro-inflammatory cyto kines,and an increase of oligodendrocyte proliferation.The trend towards decreased microglial and astrocyte reactivity as well as increased oligodendrocyte proliferation occurred with intermittent theta-burst stimulation and continuous theta-burst stimulation.Few papers analyzed the low-frequency-repetitive transcranial magnetic stimulation protocol,and the parameters evaluated were restricted to the study of astrocyte reactivity and release of pro-inflammatory cytokines,repo rting the absence of effects on these paramete rs.In what concerns the use of magnetic stimulation in unlesioned animals or cells,most articles on all four types of stimulation reported a lack of effects.It is also important to point out that the studies were developed mostly in male rodents,not evaluating possible diffe rential effects of repetitive transcranial magnetic stimulation between sexes.This systematic review supports that thro ugh modulation of glial cells repetitive magnetic stimulation contributes to the neuroprotection or repair in various neurological disease models.Howeve r,it should be noted that there are still few articles focusing on the impact of repetitive magnetic stimulation on non-neuronal cells and most studies did not perform in-depth analyses of the effects,emphasizing the need for more studies in this field.

Comparison of macular changes according to the etiology of optic neuritis:a cross-sectional study

AIM:To compare the macular structure including foveal thickness among patients with optic neuritis(ON)according to the etiology and to investigate the possible correlation between structural and visual outcomes METHODS:In this retrospective cross-sectional study,the clinical data of patients with aquaporin-4 immunoglobulin G-related ON(AQP4 group,40 eyes),myelin oligodendrocyte glycoprotein IgG-related ON(MOG group,31 eyes),and multiple sclerosis-related ON(MS group,24 eyes)were obtained.The retinal thickness of the foveal,parafoveal and perifoveal regions were measured.Visual acuity(VA),visual field index and mean deviation were measured as visual outcomes.RESULTS:The AQP4 group showed a significantly thinner fovea(226.4±13.4μm)relative to the MOG(236.8±14.0μm,P=0.015)and MS(238.9±14.3μm,P=0.007)groups.The thickness in the parafoveal area also was thinner in the AQP4 group,though the difference in perifoveal retinal thickness was not significant.Foveal thickness was correlated with VA in the AQP4 group(coefficientρ=-0.418,P=0.014),but not in the MOG and MS groups(P=0.218 and P=0.138,respectively).There was no significant correlation between foveal thickness and visual field test in all three groups.CONCLUSION:The significant thinning in the fovea and parafoveal areas in the AQP4 group compared to the MOG and MS groups are found.Additionally,macular changes in AQP4-ON show a significant correlation with VA.The results provide the possibility that retinal structural damage could reflect functional damage in AQP4-ON,distinct from MOGON and MS-ON.

Biomarkers for neuromyelitis optica:a visual analysis of emerging research trends

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system that differs from multiple sclerosis.Over the past 20 years,the search for biomarke rs for neuromyelitis optica has been ongoing.Here,we used a bibliometric approach to analyze the main research focus in the field of biomarkers for neuromyelitis optica.Research in this area is consistently increasing,with China and the United States leading the way on the number of studies conducted.The Mayo Clinic is a highly reputable institution in the United States,and was identified as the most authoritative institution in this field.Furthermore,Professor Wingerchuk from the Mayo Clinic was the most authoritative expe rt in this field.Keyword analysis revealed that the terms "neuro myelitis optica"(261 times), "multiple sclerosis"(220 times), "neuromyelitis optica spectrum disorder"(132 times), "aquaporin4"(99 times),and "optical neuritis"(87 times) were the most frequently used keywords in literature related to this field.Comprehensive analysis of the classical literature showed that the majority of publications provide conclusive research evidence supporting the use of aquaporin-4-IgG and neuromyelitis optica-IgG to effectively diagnose and differentiate neuromyelitis optica from multiple sclerosis.Furthermore,aquaporin-4-IgG has emerged as a highly specific diagnostic biomarker for neuromyelitis optica spectrum disorder.Myelin oligodendrocyte glycoprotein-IgG is a diagnostic biomarke r for myelin oligodendrocyte glycoprotein antibody-associated disease.Recent biomarkers for neuromyelitis optica in clude cerebrospinal fluid immunological biomarkers such as glial fibrillary acidic protein,serum astrocyte damage biomarkers like FAM19A5,serum albumin,and gammaaminobutyric acid.The latest prospective clinical trials are exploring the potential of these biomarkers.Preliminary results indicate that glial fibrillary acidic protein is emerging as a promising candidate biomarker for neuromyelitis optica spectrum disorder.The ultimate goal of future research is to identify non-invasive biomarkers with high sensitivity,specificity,and safety for the accurate diagnosis of neuro myelitis optica.

Three-dimensional bioprinting sodium alginate/gelatin scaffold combined with neural stem cells and oligodendrocytes markedly promoting nerve regeneration after spinal cord injury

Accumulating research has indicated that the transplantation of combined stem cells and scaffolds is an effective method for spinal cord injury(SCI).The development of three-dimensional(3D)bioprinting technology can make the 3D scaffolds combined with cells more accurate and effective for SCI treatment.However,unmyelinated newborn nerve fibers have no nerve signaling conduction,hampering recovery of motor function.In this study,we designed and printed a type of sodium alginate/gelatin scaffold loaded with neural stem cells and oligodendrocytes,which were involved in the formation of the myelin sheaths of neural cell axons.In order to observe the effectiveness of this 3D bioprinting scaffold,we transplanted it into the completely transected rat spinal cord,and then immunofluorescence staining,hematoxylin–eosin staining and behavioral assessment were performed.The results showed that this 3D bioprinting scaffold markedly improved the hindlimb motor function and promoted nerve regeneration.These findings suggested that this novel 3D bioprinting scaffold was a good carrier for cells transplantation,thereby enhancing spinal cord repair following injury.

Developmental Origins of Human Cortical Oligodendrocytes and Astrocytes

Human cortical radial glial cells are primary neural stem cells that give rise to cortical glutaminergic projection pyramidal neurons, glial cells (oligodendrocytes and astrocytes) and olfactory bulb GABAergic interneurons. One of prominent features of the human cortex is enriched with glial cells, but there are major gaps in understanding how these glial cells are generated. Herein, by integrating analysis of published human cortical single-cell RNA-Seq datasets with our immunohistochemistical analyses, we show that around gestational week 18, EGFR-expressing human cortical truncated radial glial cells (tRGs) give rise to basal multipotent intermediate progenitors (bMIPCs) that express EGFR, ASCL1, OLIG2 and OLIG1. These bMIPCs undergo several rounds of mitosis and generate cortical oligodendrocytes, astrocytes and olfactory bulb interneurons. We also characterized molecular features of the cortical tRG. Integration of our findings suggests a general picture of the lineage progression of cortical radial glial cells, a fundamental process of the developing human cerebral cortex.

Clemastine in remyelination and protection of neurons and skeletal muscle after spinal cord injury

Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.

CDP-choline to promote remyelination in multiple sclerosis:the need for a clinical trial

Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional disability.Remyelination is the natural repair process of demyelination,but it is often incomplete or fails in multiple sclerosis.Available therapies reduce the inflammatory state and prevent clinical relapses.However,therapeutic approaches to increase myelin repair in humans are not yet available.The substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular phospholipids.Regenerative properties have been shown in various animal models of diseases of the central nervous system.We have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple sclerosis.However,the results from the animal models have not yet been studied in patients with multiple sclerosis.In this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative processes.We also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.

Neural lineage differentiation of human pluripotent stem cells:Advances in disease modeling

Brain diseases affect 1 in 6 people worldwide.These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease.Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models,tissue culture models,and epidemiologic patient data that are commonly used to study brain disease.One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells(hPSCs)to neural lineages including neurons,astrocytes,and oligodendrocytes.Three-dimensional models such as brain organoids have also been derived from hPSCs,offering more physiological relevance due to their incorporation of various cell types.As such,brain organoids can better model the pathophysiology of neural diseases observed in patients.In this review,we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.