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Demyelinating diseases represent a spectrum of disorders that impose significant burden on global economy and society. Generally, the prognosis of these diseases is poor and there is no available cure. In recent decades, research has shed some light on the biology and physiology of Schwann cells and its neuroprotective effects in the peripheral ner...
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Castleman disease (CD) is a rare lymphoproliferative disorder. Two main variants have been described: unicentric or multicentric (UCD/MCD). MCD can be idiopathic or related to human herpesvirus 8 (HHV8) infection in the setting of immune deficiency. MCD is more severe than UCD and is usually accompanied by other systemic symptoms. Peripheral neurop...
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... In contrast to the ascending motor paralysis and limb involvement in Guillain-Barré syndrome, Miller-Fisher syndrome manifests in a descending pattern, beginning with dysfunction of CN III, IV and VI. 2 However, there may be an overlap between the two polyneuropathies when the motor weakness of the limbs and the respiratory system are involved in addition to the triad. 2 In Miller-Fisher syndrome, there are also reports of autonomic dysfunctions across the Guillain-Barré syndrome spectrum, including cardiac manifestations. 4 Due to its rarity, little research has been conducted regarding the appropriate treatment of Miller-Fisher syndrome-especially mild Miller-Fisher syndrome; standard Guillain-Barré syndrome treatments are typically pursued in patients with possible Miller-Fisher syndrome in the absence of known efficacy due to clinical overlap between the two conditions, with intravenous immunoglobulin being preferred clinically over plasma exchange in practice. 3,5 ...
This report describes the case of a patient who presented to the hospital with weakness, neuropathy, ataxia, and diplopia who was found to meet the criteria for Miller-Fisher syndrome but had symptoms, physical exam findings, and lab results inconsistent with typical Miller-Fisher syndrome and suggestive of a potential variant who experienced only a partial response to typical Guillain-Barré syndrome treatment.
... When an axon is injured, the Schwann cells undergo dedifferentiation and help the macrophages to clear the myelin debris that forms as a result of the injury. Once the injury site is cleared, migration of Schwann cells to the injury site occurs to remyelinate the injured axons [2,11,48]. Current treatment strategies for peripheral demyelinating diseases include cell based therapeutic approaches. Even though these existing strategies demonstrate remyelination on acute demyelination, their potential in chronic conditions remains unexplored. ...
Peripheral demyelinating diseases entail damage to axons and Schwann cells in the peripheral nervous system. Because of poor prognosis and lack of a cure, this group of diseases has a global impact. The primary underlying cause of these diseases involves the inability of Schwann cells to remyelinate the damaged insulating myelin around axons, resulting in neuronal death over time. In the past decade, extensive research has been directed in the direction of Schwann cells focusing on their physiological and neuroprotective effects on the neurons in the peripheral nervous system. One cause of dysregulation in the remyelinating function of Schwann cells has been associated with oxidative stress. Tissue-engineered biodegradable scaffolds that can stimulate remyelination response in Schwann cells have been proposed as a potential treatment strategy for peripheral demyelinating diseases. However, strategies developed to date primarily focussed on either remyelination or oxidative stress in isolation. Here, we have developed a multifunctional nanofibrous scaffold with material and biochemical cues to tackle both remyelination and oxidative stress in one matrix. We developed a nanofibrous scaffold using polycaprolactone (PCL) as a foundation loaded with antioxidant graphene oxide (GO) and coated this bioscaffold with Schwann cell acellular matrix. In vitro studies revealed both antioxidant and remyelination properties of the developed bioscaffold. Based on the results, the developed multifunctional bioscaffold approach can be a promising biomaterial approach for treating demyelinating diseases.
Graphical Abstract
... 5,6 Trauma, nerve injury, or peripheral demyelinating diseases can affect myelin, SCs, and neurons, leading to degeneration. 7,8 Interestingly, SC use has gained much popularity over the years based on their unique ability to enhance axonal migration after an injury. 3,4,[9][10][11][12] Indeed, SCs are now seen as a key cell type to be integrated in any approach aiming to repair peripheral nerve lesions. ...
In the peripheral nervous system, Schwann cells (SCs) play a crucial role in axonal growth, metabolic support of neurons and the production of myelin sheaths. Expansion of SCs after extraction from human or animal nerves is a long and often low-yielding process. We established a rapid cell culture method using a defined serum-free medium to differentiate human induced pluripotent stem cells (iPSCs) into SCs in only 21 days. The SC identity was characterized by expression of SOX10, S100b, GFAP, P75, GAP43 and EGR2 markers. The SC purity reached 87% as assessed by flow cytometry using the specific SOX10 marker, and 69% based of S100b expression. When SCs were co-cultured with iPSC-derived motor neurons in 2D or 3D, they also expressed the markers of myelin MBP, MPZ and gliomedin. Likewise, when they were seeded on the opposite side of a porous collagen sponge from motor neurons in the 3D model, they were able to migrate through it and colocalize with motor axons after 8 weeks of maturation. Moreover, they were shown by transmission electron microscopy to form myelin sheaths around motor axons. These results suggest that the use of autologous iPSC-derived SCs for clinical applications such as the repair of peripheral nerve damage, the treatment The SC identity was characterized by expression of SOX10, GFAP, P75 and EGR2 markers. The SC purity was assessed by flow cytometry using the specific SOX10 marker and reached 87%. When SCs were co-cultured with iPSC-derived motor neurons in 2D or 3D, they also expressed the markers of myelin MBP, MPZ and gliomedin. Likewise, when they were seeded on the opposite side of a porous collagen sponge from motor neurons in the 3D model, they were able to migrate through it and colocalize with motor axons after 8 weeks of maturation. Moreover, they were shown by transmission electron microscopy to form myelin sheaths around motor axons. These results suggest that the use of autologous iPSC-derived SCs for clinical applications such as the repair of peripheral nerve damage, the treatment of spinal cord injuries or for demyelinating diseases could be a valuable option.
... Myelination is a process by which SC in the PNS produce the myelin sheath around the axonal membrane [12]. In peripheral nerve injury, SC play a major role in several aspects of nerve repair such as degeneration and remyelination [55]. ...
Old world alphaviruses (e.g., chikungunya) are known to cause severe acute and chronic debilitating arthralgia/arthritis. However, atypical neurological manifestations and, in particular, unexpected cases of acute inflammatory Guillain–Barre syndrome (GBS) have been associated with the arthritogenic alphaviruses. The pathogenesis of alphavirus-associated GBS remains unclear. We herein addressed for the first time the role of Schwann cells (SC) in peripheral neuropathy post-alphaviral infection using the prototypical ONNV alphavirus model. We demonstrated that human SC expressed the recently identified alphavirus receptor MxRA8 and granting viral entry and robust replication. A canonical innate immune response was engaged by ONNV-infected SC with elevated gene expression for RIG-I, MDA5, IFN-β, and ISG15 and inflammatory chemokine CCL5. Transcription levels of prostaglandin E2-metabolizing enzymes including cPLA2α, COX-2, and mPGES-1 were also upregulated in ONNV-infected SC. Counterintuitively, we found that ONNV failed to affect SC regenerative properties as indicated by elevated expression of the pro-myelinating genes MPZ and MBP1 as well as the major pro-myelin transcription factor Egr2. While ONNV infection led to decreased expression of CD55 and CD59, essential to control complement bystander cytotoxicity, it increased TRAIL expression, a major pro-apoptotic T cell signal. Anti-apoptotic Bcl2 transcription levels were also increased in infected SC. Hence, our study provides new insights regarding the remarkable immunomodulatory role of SC of potential importance in the pathogenesis of GBS following alphavirus infection.
... The onset is gradual, and it disproportionately affects people of a given age range [224,225]. The resistant framework assaults and obliterates the myelin sheath of the PNS, causing demyelination and axonal degeneration in fragments [226]. Histological outcomes from the CIDP show a meager myelin sheath with more limited internodes, commonly referred to as onion bulbs. ...
... Histological outcomes from the CIDP show a meager myelin sheath with more limited internodes, commonly referred to as onion bulbs. The slow nerve conduction rate, which indicates conduction block, indicates demyelination [226]. Autoimmunity to neurofascin-155 (NF155) and contactin-1 (CNTN1) has recently been discovered in a large number of patients [227,228]. ...
... CIDP symptoms appear gradually but steadily, with neurological impairments peaking after 8 weeks of disease initiation [223]. There are a number of signs and symptoms, such as tingling and numbness in the extremities, symmetrical slug-gishness and paresthesia in the arms and legs, fatigue, ataxia, and limb incoordination [226]. Therapy with oral glucocorticoids usually results in a positive outcome. ...
Based on the diverse physiological influence, the impact of glial cells has become much more evident on neurological illnesses, resulting in the origins of many diseases appearing to be more convoluted than previously happened. Since neurological disorders are often random and unknown, hence the construction of animal models is difficult to build, representing a small fraction of people with a gene mutation. As a result, an immediate necessity is grown to work within in vitro techniques for examining these illnesses. As the scientific community recognizes cell-autonomous contributions to a variety of central nervous system illnesses, therapeutic techniques involving stem cells for treating neurological diseases are gaining traction. The use of stem cells derived from a variety of sources is increasingly being used to replace both neuronal and glial tissue. The brain’s energy demands necessitate the reliance of neurons on glial cells in order for it to function properly. Furthermore, glial cells have diverse functions in terms of regulating their own metabolic activities, as well as collaborating with neurons via secreted signaling or guidance molecules, forming a complex network of neuron-glial connections in health and sickness. Emerging data reveals that metabolic changes in glial cells can cause morphological and functional changes in conjunction with neuronal dysfunction under disease situations, highlighting the importance of neuron-glia interactions in the pathophysiology of neurological illnesses. In this context, it is required to improve our understanding of disease mechanisms and create potential novel therapeutics. According to research, synaptic malfunction is one of the features of various mental diseases, and glial cells are acting as key ingredients not only in synapse formation, growth, and plasticity but also in neuroinflammation and synaptic homeostasis which creates critical physiological capacity in the focused sensory system. The goal of this review article is to elaborate state-of-the-art information on a few glial cell types situated in the central nervous system (CNS) and highlight their role in the onset and progression of neurological disorders.
... Perhaps the most frequently referenced of these is multiple sclerosis (MS), others include neuromyelitis optica (NMO), acute disseminating encephalomyelitis (ADEM), transverse myelitis, and optic neuritis480,486 . The myelinating Schwann cells of the peripheral nervous system (PNS) can be affected in a related manner, such as in the example of Guillain-Barre Syndrome (GBS), peripheral neuropathy, and Charcot-Marie-Tooth disease487 . Similarly, to MS, the exact aetiology of such disorders is not fully understood, however recurring trends in the literature would suggest an infectious event preceding disease onset. ...
... Similarly, to MS, the exact aetiology of such disorders is not fully understood, however recurring trends in the literature would suggest an infectious event preceding disease onset. In the case of Guillain-Barre syndrome, around 60% of incidence is preceded by, or associated with, Campylobacter jejuni infection487 . In other cases, onset has been associated with infection by numerous viruses in the period preceding clinical symptoms, these include; Zika virus 488 , Hepatitis E 489 , human immunodeficiency virus (HIV) 490 , Epstein-Barr virus (EBV) 491 , varicella-zoster virus (VZV)492 , and influenza493 . ...
Helicobacter pylori colonises the stomachs of almost half the world’s population, subverting host immunity to usually establish a life-long infection. Although asymptomatic in most cases, peptic ulcer disease and gastric cancer develop in a minority of those colonised. Recently, more evidence is emerging that the reducing prevalence of infections in developed countries is linked with the stark rise of allergy, asthma, and autoimmune diseases such as multiple sclerosis (MS). The ‘Old friend’s hypothesis’, suggests that the lack of exposure to certain microbes, likely by increasing antibiotic use and improved sanitation, causes dysregulated immunity leading to immune and inflammatory conditions. The microbiota also regulates host immunity, during homeostasis and in the response to infection and susceptibility for disease development. The induction of tolerogenic dendritic cells and IL-10-producing regulatory T-cells, is an important H. pylori persistence mechanism. In the literature, these responses are also linked to the mitigation of extra-gastric diseases. Inadequate Treg responses are associated with a negative prognosis, especially in MS. This is the most common neurological condition affecting young adults, causing chronic progressive disability with a devastating impact on quality of life. Using the mouse model experimental autoimmune encephalomyelitis (EAE), the research group previously reported a reduced severity of EAE when infected with H. pylori. For the current studies, it was hypothesised that protection from MS may be mediated through H. pylori modulation of the T-helper response. Gastric mucosal inflammation induced by H. pylori may alter lymphocyte homing patterns and reduce infiltration to the central nervous system. The regulatory T-cell response has previously been shown to facilitate repair in a demyelinated central nervous system by the secreted factor CCN3. This was proposed as a potential mechanism for H. pylori to mediate a protective effect in EAE or MS. Murine glia were cultured with CD4 supernatants to investigate the myelinating capacity of oligodendrocytes. Firstly, differences in the peripheral blood T-helper and cytokine responses were investigated between infected and uninfected patients, and infected patients before and after H. pylori eradication therapy. Differences in IL-17A, IL-12p70 and IL-10 concentrations were detected according to presence of H. pylori infection and gastro-duodenal pathology. The CD4+ T-helper cytokines IL10 and IL17A were differentially expressed at the mRNA level in PBMCs between infected and uninfected patients. IL10 mRNA was elevated following H. pylori eradication, concurrent with a reducing anti-Hp humoral IgG response. This indicates that the infection exerts important effects on the immune system. Using the EAE model, a strain-specific mitigation of disease severity was observed when infected with H. pylori strain SS1 compared to PMSS1, independently of the CD4 T-helper subsets quantified. A fluorescence-based technique was developed for in vivo imaging of EAE CD4+ T-cells adoptively transferred to infected or uninfected recipient mice. The CD4+ T-cell populations from the spleens and mesenteric lymph nodes of H. pylori infected mice contained higher frequencies of both pro- and anti-inflammatory T-helper subsets. CCN3 mRNA was markedly elevated in cells from infected mice. There was a marked increase in myelin production from glia treated with supernatants from CD4 cells, and this was slightly higher using the cell supernatants from infected mice. The differences observed were modest, and further work is required to confirm and expand on these preliminary findings.
... Seven out of eight patients (87.5%) had diffused demyelinating polyneuropathy with axonal loss consistent with the findings by Sung et al. and in China (98.8%) [6,7,13,25]. While 29 patients were subjected to VEGF test in China and all cases in the Japanese study, only 1 out of the 2 who had test for VEGF levels was elevated. ...
To determine and analyze the clinical characteristics of POEMS syndrome among Southeast Asian countries. We searched the literature using a pre-specified inclusion and exclusion criteria and using the search terms "[(POEMS) or (Takatsuki) or (PEP) or (Crow Fukase) and (syndrome)] AND [Countries/People of Southeast Asia]". Seven studies, including 5 case reports, 1 case series, and 1 correspondence letter containing 8 patients, were eligible for analysis. The median age of onset was 54 years, while the median duration to correct diagnosis was 5.5 months. The most common initial presentation was weakness (4/6) with 50% initially diagnosed as chronic inflammatory demyelinating polyneuropathy. On physical examination , 100% had evidence of length dependent polyneuropathy, 80% had papilledema, 75% had edema/effusion, 86% had skin changes, and 67% had organomegaly. All had abnormal NCS and CT scan while 1 tested negative for monoclonal gammopathy restricted to lambda. Only 2 had VEGF results, one of which was normal. Melphalan and steroid combination was the most common treatment given with only 1 case dying of sepsis. Although the number of cases in Southeast Asia is lower, which can be attributed to difference in ethnicity and geographical location, the presenting signs and symptoms of this condition were similar to other countries. However, the new proposed criteria may not be applicable in the region as only few countries are capable of VEGF testing.
... The myelin sheath plays several important roles in the proper function of neurons: it maintains saltatory conduction during neuronal transmission, supports neurons by providing trophic factors and assists in regeneration [1][2][3]. Therefore, the loss of myelin in the peripheral nervous system (PNS) can lead to demyelinating neuropathies, causing muscular atrophy, foot deformities, paresthesia, numbness and paralysis [4]. For example, Charcot-Marie-Tooth (CMT) disease is one of the most commonly inherited neuropathies worldwide and constitutes majority of all demyelinating PNS neuropathies [5]. ...
... In several demyelinating peripheral neuropathies, the distal region of the axon is relatively more demyelinated than the proximal, making the symptoms such as muscle atrophy and numbness exacerbated in the distal region of the limb [4,36,37]. As such, an optimal treatment for these neuropathies should enhance myelination comparatively more in the distal region than in the proximal. ...
As the myelin sheath is crucial for neuronal saltatory conduction, loss of myelin in the peripheral nervous system (PNS) leads to demyelinating neuropathies causing muscular atrophy, numbness, foot deformities and paralysis. Unfortunately, few interventions are available for such neuropathies, because previous pharmaceuticals have shown severe side effects and failed in clinical trials. Therefore, exploring new strategies to enhance PNS myelination is critical to provide solution for such intractable diseases. This study aimed to investigate the effectiveness of electrical stimulation (ES) to enhance myelination in the mouse dorsal root ganglion (DRG)—an ex vivo model of the PNS. Mouse embryonic DRGs were extracted at E13 and seeded onto Matrigel-coated surfaces. After sufficient growth and differentiation, screening was carried out by applying ES in the 1–100 Hz range at the beginning of the myelination process. DRG myelination was evaluated via immunostaining at the intermediate (19 days in vitro (DIV)) and mature (30 DIV) stages. Further biochemical analyses were carried out by utilizing ribonucleic acid sequencing, quantitative polymerase chain reaction and biochemical assays at both intermediate and mature myelination stages. Imaging of DRG myelin lipids was carried out via time-of-flight secondary ion mass spectrometry (ToF-SIMS). With screening ES conditions, optimal condition was identified at 20 Hz, which enhanced the percentage of myelinated neurons and average myelin length not only at intermediate (129% and 61%) but also at mature (72% and 17%) myelination stages. Further biochemical analyses elucidated that ES promoted lipid biosynthesis in the DRG. ToF-SIMS imaging showed higher abundance of the structural lipids, cholesterol and sphingomyelin, in the myelin membrane. Therefore, promotion of lipid biosynthesis and higher abundance of myelin lipids led to ES-mediated myelination enhancement. Given that myelin lipid deficiency is culpable for most demyelinating PNS neuropathies, the results might pave a new way to treat such diseases via electroceuticals.
... Accordingly, SC metabolism is essential for axonal integrity and survival (Funfschilling et al., 2012;Viader et al., 2011b). Evidence that genetic mutations, toxins, or autoantibodies affecting SC function and/or integrity are responsible for, or contribute to, a series of detrimental neurological conditions compromising PNS activity further support the relevance of these cells for peripheral nerve functionality (Kamil et al., 2019;Valentine, 2020). ...
Schwann cells (SCs) are fundamental components of the peripheral nervous system (PNS) of all vertebrates and play essential roles in development, maintenance, function, and regeneration of peripheral nerves. There are distinct populations of SCs including: (1) myelinating SCs that ensheath axons by a specialized plasma membrane, called myelin, which enhances the conduction of electric impulses; (2) non-myelinating SCs, including Remak SCs, which wrap bundles of multiple axons of small caliber, and perysinaptic SCs (PSCs), associated with motor axon terminals at the neuromuscular junction (NMJ). All types of SCs contribute to PNS regeneration through striking morphological and functional changes in response to nerve injury, are affected in peripheral neuropathies and show abnormalities and a diminished plasticity during aging. Therefore, methodological approaches to study and manipulate SCs in physiological and pathophysiological conditions are crucial to expand the present knowledge on SC biology and to devise new therapeutic strategies to counteract neurodegenerative conditions and age-derived denervation. We present here an updated overview of traditional and emerging methodologies for the study of SCs for scientists approaching this research field.
... Fig.1 shows a graphic configuration of a nerve fiber in which AP conduction through myelin sheath is highlighted schematically. Demyelination of nerve fibers also leads to losing nerve pulses in the central nervous system, and a discontinuity in signaling may result in cell death [16], [17]. Detecting the tiny level of demyelination on the nerve fiber before progression can lead to early diagnosis of some mental disorders and help for prevention of disease development using effective drug plans. ...
The myelin sheath, as an insulation layer in nerve cells, plays an essential role in neural communication and signal conduction. Loss of myelin, referred to as demyelination, is associated with many mental disorders. Detecting the tiny demyelinated parts in nerve fibers can provide early diagnosis of some mental disorders and create effective treatment plans. This paper establishes a new engineering approach for differentiation between demyelinated and myelinated axons by analyzing spectral responses resulting from the optical simulation framework. We propose computational modeling on the photonic communication of nerve fibers and develop a graphene-based neurophotonic device that can be used to detect the regions demyelinated on the nerve fiber. We first model a nanoscale thin-film configuration of the multilayered myelinated axon to evaluate photons transmission in the nerve fibers under geometric defects as demyelination. Then, the nerve’s optical characteristics are achieved by focusing on the reflectance of light incidence on the nerve model with the change of the demyelination size to distinguish demyelinated—from myelinated nerves by the spectral contrast. Undertaking the different levels of demyelination progression, we theoretically explore the variations of effective refractive index using an analytical solution technique. Ultimately, we design a nanostructure configured with silicon dioxide, graphene, and gold nanoparticles to function as a biochip recognizing myelinated axon damage under the surface plasmon effect. This device can promote a practical procedure to distinguish nanoscale demyelinated and myelinated axons, which can be utilized for neural sensing of tiny brain tissues as a neurophotonic needle.
