p62/sequestosome-1 as a severity-reflecting plasma biomarker in Charcot-Marie-Tooth disease type 1A.

Autophagy is a self-degradation system for recycling to maintain homeostasis. p62/sequestosome-1 (p62) is an autophagy receptor that accumulates in neuroglia in neurodegenerative diseases. The objective of this study was to determine the elevation of plasma p62 protein levels in patients with Charcot-Marie-Tooth disease 1A (CMT1A) for its clinical usefulness to assess disease severity. We collected blood samples from 69 CMT1A patients and 59 healthy controls. Plasma concentrations of p62 were analyzed by ELISA, and we compared them with Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2). A mouse CMT1A model (C22) was employed to determine the source and mechanism of plasma p62 elevation. Plasma p62 was detected in healthy controls with median value of 1978 pg/ml, and the levels were significantly higher in CMT1A (2465 pg/ml, p < 0.001). The elevated plasma p62 levels were correlated with CMTNSv2 (r = 0.621, p < 0.0001), motor nerve conduction velocity (r = - 0.490, p < 0.0001) and disease duration (r = 0.364, p < 0.01). In C22 model, increased p62 expression was observed not only in pathologic Schwann cells but also in plasma. Our findings indicate that plasma p62 measurement could be a valuable tool for evaluating CMT1A severity and Schwann cell pathology.

The Influence of Lysosomal Stress on Dental Pulp Stem Cell-Derived Schwann Cells.

BACKGROUND: Dysregulation of the endo-lysosomal-autophagy pathway has been identified as a critical factor in the pathology of various demyelinating neurodegenerative diseases, including peripheral neuropathies. This pathway plays a crucial role in transporting newly synthesized myelin proteins to the plasma membrane in myelinating Schwann cells, making these cells susceptible to lysosome-related dysfunctions. Nevertheless, the specific impact of lysosomal dysfunction in Schwann cells and its contribution to neurodegeneration remain poorly understood. METHODS: We aim to mimic lysosomal dysfunction in Schwann cells using chloroquine, a lysosomal dysfunction inducer, and to monitor lysosomal leakiness, Schwann cell viability, and apoptosis over time. Additionally, due to the ethical and experimental issues associated with cell isolation and the culturing of human Schwann cells, we use human dental pulp stem cell-derived Schwann cells (DPSC-SCs) as a model in our study. RESULTS: Chloroquine incubation boosts lysosomal presence as demonstrated by an increased Lysotracker signal. Further in-depth lysosomal analysis demonstrated an increased lysosomal size and permeability as illustrated by a TEM analysis and GAL3-LAMP1 staining. Moreover, an Alamar blue assay and Caspase-3 staining demonstrates a reduced viability and increased apoptosis, respectively. CONCLUSIONS: Our data indicate that prolonged lysosomal dysfunction leads to lysosomal permeability, reduced viability, and eventually apoptosis in human DPSC-SCs.

Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFß Signaling in a Model of Perineural Invasion.

The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial-mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFß receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFß signaling in regulating this process.

Schwann cells in pancreatic cancer: Unraveling their multifaceted roles in tumorigenesis and neural interactions.

Pancreatic ductal adenocarcinoma (PDAC), characterized by heightened neural density, presents a challenging prognosis primarily due to perineural invasion. Recognized for their crucial roles in neural support and myelination, Schwann cells (SCs) significantly influence the process of tumorigenesis. This review succinctly outlines the interplay between PDAC and neural systems, positioning SCs as a nexus in the tumor-neural interface. Subsequently, it delves into the cellular origin and influencers of SCs within the pancreatic tumor microenvironment, emphasizing their multifaceted roles in tumor initiation, progression, and modulation of the neural and immune microenvironment. The discussion encompasses potential therapeutic interventions targeting SCs. Lastly, the review underscores pressing issues, advocating for sustained exploration into the diverse contributions of SCs within the intricate landscape of PDAC, with the aim of enhancing our understanding of their involvement in this complex malignancy.

Schwann cell derived pleiotrophin stimulates fibroblast for proliferation and excessive collagen deposition in plexiform neurofibroma.

Neurofibromatosis type 1 associated plexiform neurofibroma (pNF) is characterized by abundant fibroblasts and dense collagen, yet the intricate interactions between tumor-origin cells (Schwann cells) and neurofibroma-associated fibroblasts (NFAFs) remain elusive. Employing single-cell RNA sequencing on human pNF samples, we generated a comprehensive transcriptomics dataset and conducted cell-cell communication analysis to unravel the molecular dynamics between Schwann cells and NFAFs. Our focus centered on the pleiotrophin (PTN)/nucleolin (NCL) axis as a pivotal ligand-receptor pair orchestrating this interaction. Validation of PTN involvement was affirmed through coculture models and recombinant protein experiments. Functional and mechanistic investigations, employing assays such as CCK8, EdU, Western Blot, ELISA, Hydroxyproline Assay, and Human phospho-kinase array, provided critical insights. We employed siRNA or inhibitors to intercept the PTN/NCL/proline-rich Akt substrate of 40 kDa (PRAS40) axis, validating the associated molecular mechanism. Our analysis highlighted a subset of Schwann cells closely linked to collagen deposition, underscoring their significance in pNF development. The PTN/NCL axis emerged as a key mediator of the Schwann cell-NFAF interaction. Furthermore, our study demonstrated that elevated PTN levels enhanced NFAF proliferation and collagen synthesis, either independently or synergistically with TGF-ß1 in vitro. Activation of the downstream molecule PRAS40 was noted in NFAFs upon PTN treatment. Crucially, by targeting NCL and PRAS40, we successfully reversed collagen synthesis within NFAFs. In conclusion, our findings unveil the pivotal role of the PTN/NCL/PRAS40 axis in driving pNF development by promoting NFAFs proliferation and function. Targeting this pathway emerges as a potential therapeutic strategy for pNF. This study contributes novel insights into the molecular mechanisms governing pNF pathogenesis.

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. METHODS: We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. RESULTS: Intraepidermal Schwann cells were detected in human skin of the finger-but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other-but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. CONCLUSIONS: Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

Mucosal Schwann cell hamartoma: a benign and little-known entity.

Dear editor, 50 years-old female with personal history of mutation of the gene BRCA1 and previous prophylactic double anexectomy consulted for rectal bleeding without pain since two weeks. A blood test was performed, with hemoglobin levels of 13.1g/dl and without iron deficiency. In the anal inspection there were neither external hemorrhoids nor anal fistulas, so a colonoscopy was requested. In the colonoscopy, all the colon mucosa was normal but, in the rectal retroflexion, apart from internal engorged hemorrhoids, surrounding the 50% of the anal opening an erythematous and indurated mucosa was found (figure 1). Biopsies were taken. The pathology report informed of proliferation of spindle-shaped cells exclusively in the lamina propria with eosinophilic cytoplasm and unclear cell borders (figure 2). Not nuclear atypia or mitotic activity were observed. On immunohistochemistry, S-100 protein was strongly positive (figure 3) and CD34, SMA, EMA and c-kit were negative. These results are concordant with the diagnosis of Schwann cells in the context of a mucosal Schwann cell hamartoma (MSCH). Given that these lesions seem to not have malignant potential, the patient was discharged without control colonoscopies. The episodes of rectorrhagia were attributed to the presence of internal hemorrhoids. Discussion: MSCH are benign and intramucosal tumors with a mesenchymal origin. They are most commonly located in the distal colon, but they were also found in the gallbladder, the esophagogastric union and in the antrum. They are observed most frequently in middle aged women (around 60 years-old) and they are generally asymptomatic. They are presented as polyps between 1 and 6mm, but in other cases they appeared as small whitish nodules, protruding lesions with normal superficial mucosa or even they were found in random biopsies of the colon. The MSCH are a rare entity with an unknown prevalence. Less than 100 cases are described in the literature. It is essential the differentiation between this entity and the Schwanomas or the gastrointestinal stromal tumors (GIST). Schwanomas are rare in the colon, they are well circumscribed (in contrast with the MSCH) and they are not limited to the lamina propria. GIST are more frequently located in the stomach and they are positive for c-kit. MSCH are not associated with hereditary syndromes such as neurofibromatosis and, in contrast with Schwanomas or GIST, they do not require surveillance because they are benign.

Single-cell transcriptomes reveal the heterogeneity and microenvironment of vestibular schwannoma.

BACKGROUND: Vestibular schwannoma (VS) is the most common benign tumor in the cerebellopontine angle and internal auditory canal. Illustrating the heterogeneous cellular components of VS could provide insights into its various growth patterns. METHODS: Single-cell RNA sequencing was used to profile transcriptomes from 7 VS samples and 2 normal nerves. Multiplex immunofluorescence was employed to verify the data set results. Bulk RNA sequencing was conducted on 5 normal nerves and 44 VS samples to generate a prediction model for VS growth. RESULTS: A total of 83 611 cells were annotated as 14 distinct cell types. We uncovered the heterogeneity in distinct VS tumors. A subset of Schwann cells with the vascular endothelial growth factor biomarker was significantly associated with fast VS growth through mRNA catabolism and peptide biosynthesis. The macrophages in the normal nerves were largely of the M2 phenotype, while no significant differences in the proportions of M1 and M2 macrophages were found between slow-growing and fast-growing VS. The normal spatial distribution of fibroblasts and vascular cells was destroyed in VS. The communications between Schwann cells and vascular cells were strengthened in VS compared with those in the normal nerve. Three cell clusters were significantly associated with fast VS growth and could refine the growth classification in bulk RNA. CONCLUSIONS: Our findings offer novel insights into the VS microenvironment at the single-cell level. It may enhance our understanding of the different clinical phenotypes of VS and help predict growth characteristics. Molecular subtypes should be included in the treatment considerations.

Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by perineural invasion (PNI), which is associated with excruciating neuropathic pain and malignant progression. However, the relationship between PNI and tumour stromal cells has not been clarified. METHODS: The dorsal root ganglia or sciatic nerves nerve model was used to observe the paracrine interaction and the activation effect among Schwann cells, tumour-associated macrophages (TAMs), and pancreatic cancer cells in vitro. Next generation sequencing, enzyme-linked immunosorbent assay and chromatin immunoprecipitation were used to explore the specific paracrine signalling between TAMs and Schwann cells. RESULTS: We demonstrated that more macrophages were expressed around nerves that have been infiltrated by pancreatic cancer cells compared with normal nerves in murine and human PNI specimens. In addition, high expression of CD68 or GFAP is associated with an increased incidence of PNI and indicates a poor 5-year survival rate in patients with PDAC. Mechanistically, tumour-associated macrophages (TAMs) activate Schwann cells via the bFGF/PI3K/Akt/c-myc/GFAP pathway. Schwann cells secrete IL-33 to recruit macrophages into the perineural milieu and facilitate the M2 pro-tumourigenic polarisation of macrophages. CONCLUSIONS: Our study demonstrates that the bFGF/IL-33 positive feedback loop between Schwann cells and TAMs is essential in the process of PNI of PDAC. The bFGF/PI3K/Akt/c-myc/GFAP pathway would open potential avenues for targeted therapy of PDAC.

[Research advances on the role of Schwann cells in diabetic peripheral neuropathy].

Diabetic peripheral neuropathy (DPN) is one of the common chronic complications of diabetes, resulting in neuropathy of spinal nerve, cranial nerve, and vegetative nerve. Diabetic distal symmetric multiple neuropathy is the most representative lesion of DPN, including symptoms of bilateral limbs pain, numbness, and paresthesia, etc. DPN is one of the main reasons causing diabetic foot ulcer (DFU). Schwann cells (SCs) are the primary glia cells of the peripheral nervous system, which play very important role in repairing after nerve injury. As the target cells of chronic hyperglycemia, SCs' functions, including the formation of myelin sheath, the secretion of neurotrophic factors, energy supplying for the axon, and the guidance of axon regeneration, etc., are damaged under the action of high glucose. The destroyed functions of SCs can inhibit the repair of damaged nerves and accelerate the progress of DPN. Therefore, if the damage of high glucose to SCs can be effectively reduced, it will provide a new way for the treatment of DPN and DFU and reduce the morbidity of DFU. This review focuses on the function of SCs and its relationship with DPN.

Structural changes in Schwann cells and nerve fibres in type 1 diabetes: relationship with diabetic polyneuropathy.

AIMS/HYPOTHESIS: Our aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic polyneuropathy. We also aimed to investigate the relationship between these changes and peripheral neuropathic symptoms in type 1 diabetes. METHODS: Skin biopsies (3 mm) taken from carefully phenotyped participants with type 1 diabetes without polyneuropathy (T1D, n=25), type 1 diabetes with painless diabetic polyneuropathy (T1DPN, n=30) and type 1 diabetes with painful diabetic polyneuropathy (P-T1DPN, n=27), and from healthy control individuals (n=25) were immunostained with relevant antibodies to visualise SCs and nerve fibres. Stereological methods were used to quantify the expression of cutaneous SCs and nerve fibres. RESULTS: There was a difference in the number density of nSCs not abutting to nerve fibres between the groups (p=0.004) but not in the number density of nSCs abutting to nerve fibres, nor in solitary or total subepidermal SC soma number density. The overall dermal SC expression (measured by dermal SC area fraction and subepidermal SC process density) and peripheral nerve fibre expression (measured by intraepidermal nerve fibre density, dermal nerve fibre area fraction and subepidermal nerve fibre density) differed between the groups (all p<0.05): significant differences were seen in participants with T1DPN and P-T1DPN compared with those without diabetic polyneuropathy (healthy control and T1D groups) (all p<0.05). No difference was found between participants in the T1DPN and P-T1DPN group, nor between participants in the T1D and healthy control group (all p>0.05). Correlational analysis showed that cutaneous SC processes and nerve fibres were highly associated, and they were weakly negatively correlated with different neuropathy measures. CONCLUSIONS/INTERPRETATION: Cutaneous SC processes and nerves, but not SC soma, are degenerated and interdependent in individuals with diabetic polyneuropathy. However, an increase in structurally damaged nSCs was seen in individuals with diabetic polyneuropathy. Furthermore, dermal SC processes and nerve fibres correlate weakly with clinical measures of neuropathy and may play a partial role in the pathophysiology of diabetic polyneuropathy in type 1 diabetes.

Regenerative Strategies in Treatment of Peripheral Nerve Injuries in Different Animal Models.

BACKGROUND: Peripheral nerve damage mainly resulted from traumatic or infectious causes; the main signs of a damaged nerve are the loss of sensory and/or motor functions. The injured nerve has limited regenerative capacity and is recovered by the body itself, the recovery process depends on the severity of damage to the nerve, nowadays the use of stem cells is one of the new and advanced methods for treatment of these problems. METHOD: Following our review, data are collected from different databases "Google scholar, Springer, Elsevier, Egyptian Knowledge Bank, and PubMed" using different keywords such as Peripheral nerve damage, Radial Nerve, Sciatic Nerve, Animals, Nerve regeneration, and Stem cell to investigate the different methods taken in consideration for regeneration of PNI. RESULT: This review contains tables illustrating all forms and types of regenerative medicine used in treatment of peripheral nerve injuries (PNI) including different types of stem cells " adipose-derived stem cells, bone marrow stem cells, Human umbilical cord stem cells, embryonic stem cells" and their effect on re-constitution and functional recovery of the damaged nerve which evaluated by physical, histological, Immuno-histochemical, biochemical evaluation, and the review illuminated the best regenerative strategies help in rapid peripheral nerve regeneration in different animal models included horse, dog, cat, sheep, monkey, pig, mice and rat. CONCLUSION: Old surgical attempts such as neurorrhaphy, autogenic nerve transplantation, and Schwann cell implantation have a limited power of recovery in cases of large nerve defects. Stem cell therapy including mesenchymal stromal cells has a high potential differentiation capacity to renew and form a new nerve and also restore its function.

Exosomes derived from schwann cells alleviate mitochondrial dysfunction and necroptosis after spinal cord injury via AMPK signaling pathway-mediated mitophagy.

Although spinal cord injury (SCI) represents a primary etiology of disability, currently, there are exist limited viable therapies modalities. Acquiring comprehension of the diverse pathways that drive mitochondrial aberration may facilitate the identification of noteworthy targets for ameliorating the deleterious consequences precipitated by SCI. Our objective was to determine the efficiency of exosomes produced from Schwann cells (SCDEs) in protecting against mitochondrial dysfunction. This evaluation was conducted using a rat model of compressed SCI and in vitro experiments involving rat pheochromocytoma cells (PC12) exposed to oxygen-glucose deprivation (OGD). The conducted experiments yielded evidence that SCDEs effectively mitigated oxidative stress (OS) and inflammation subsequent to SCI, while concurrently diminishing necroptosis. Subsequent in vitro inquiry assessed the impact of SCDEs on PC12, with a specific emphasis on mitochondrial functionality, necrotic cell prevalence, and mitophagy. The study findings revealed that SCDEs enhanced mitophagy in PC12 cells, leading to a decrease in the generation of reactive oxygen species (ROS) and inflammatory cytokines (CK) provoked by OGD-induced injury. This, in turn, mitigated mitochondrial dysfunction and necroptosis. Mechanistically, SCDEs facilitated cellular mitophagy through activation of the AMPK signaling pathway. In conclusion, our data strongly support the notion that SCDEs hold considerable promise as a therapeutic approach for managing SCI. Furthermore, our investigation serves to elucidate the pivotal role of AMPK-mediated mitophagy in reducing cell damage, thereby unveiling novel prospects for enhancing neuro-pathological outcomes following SCI.

Rare giant schwannoma of superficial peroneal nerve on the dorsum of foot.

Schwannoma is a benign tumour of Schwann cells originating from myelin sheath of axons of the nerves. It is usually seen in the vestibular region, very rarely found in extremity regions. Schwannomas are termed 'Giant' when they measure more than five centimetres in a minimum of one dimension. Giant schwannomas in the foot and ankle region are extremely uncommon. Only eight cases of such a condition are reported. This is a case report of a giant schwannoma found arising from the superficial peroneal nerve in the dorsolateral aspect of the foot. This swelling was excised completely and the diagnosis was confirmed by histopathology.

Function Follows Form: Oriented Substrate Nanotopography Overrides Neurite-Repulsive Schwann Cell-Astrocyte Barrier Formation in an In Vitro Model of Glial Scarring.

Schwann cell (SC) transplantation represents a promising therapeutic approach for traumatic spinal cord injury but is frustrated by barrier formation, preventing cell migration, and axonal regeneration at the interface between grafted SCs and reactive resident astrocytes (ACs). Although regenerating axons successfully extend into SC grafts, only a few cross the SC-AC interface to re-enter lesioned neuropil. To date, research has focused on identifying and modifying the molecular mechanisms underlying such scarring cell-cell interactions, while the influence of substrate topography remains largely unexplored. Using a recently modified cell confrontation assay to model SC-AC barrier formation in vitro, highly oriented poly(ε-caprolactone) nanofibers were observed to reduce AC reactivity, induce extensive oriented intermingling between SCs and ACs, and ultimately enable substantial neurite outgrowth from the SC compartment into the AC territory. It is anticipated that these findings will have important implications for the future design of biomaterial-based scaffolds for nervous tissue repair.

Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis.

AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and 'dying-back' pathology in models of SOD1-dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP-43, a key mediator protein in ALS, is overexpressed in neurons in Thy1-hTDP-43WT mice. We therefore aimed to comprehensively analyse NMJ pathology in this model of ALS. METHODS: Expression of TDP-43 was assessed via western blotting. Immunohistochemistry techniques, alongside NMJ-morph quantification, were used to analyse motor neuron number, NMJ denervation status and terminal Schwann cell morphology. RESULTS: We present a time course of progressive, region-specific motor neuron pathology in Thy1-hTDP-43WT mice. Thy1-driven hTDP-43 expression increased steadily, correlating with developing hindlimb motor weakness and associated motor neuron loss in the spinal cord with a median survival of 21 days. Pronounced NMJ denervation was observed in hindlimb muscles, mild denervation in cranial muscles but no evidence of denervation in either forelimb or trunk muscles. NMJ pathology was restricted to motor nerve terminals, with denervation following the same time course as motor neuron loss. Terminal Schwann cells were lost from NMJs in hindlimb muscles, directly correlating with denervation status. CONCLUSIONS: Thy1-hTDP-43WT mice represent a severe model of ALS, with NMJ pathology/denervation of distal muscles and motor neuron loss, as observed in ALS patients. This model therefore provides an ideal platform to investigate mechanisms of dying-back pathology, as well as NMJ-targeting disease-modifying therapies in ALS.

Metformin promotes Schwann cell remyelination, preserves neural tissue and improves functional recovery after spinal cord injury.

Patients with a spinal cord injury (SCI) usually suffer lifelong disability as a result. Considering this, SCI treatment and pathology study are urgently needed. Metformin, a widely used hypoglycemic drug, has been indicated for its important role in central nervous system diseases. This study aimed to investigate the potential effect of metformin on remyelination after SCI. In the present study, we established a cervical contusion SCI model and metformin treatment was applied after SCI. Biomechanical parameters and behavioral assessment were used to evaluate the severity of injury and the improvement of functional recovery after SCI, respectively. The immunofluorescence and western blot were performed at the terminal time point. Our results showed that treating with metformin after SCI improved functional recovery by reducing the white matter loss and promoting Schwann cell remyelination, and the Nrg1/ErbB signaling pathway may be involved in promoting remyelination mediated by oligodendrocytes and Schwann cells. In addition, the area of spared tissues was significantly increased in the metformin group. However, metformin had no significant effects on the glial scar and inflammation after SCI. In summary, these findings indicated that the role of metformin in Schwann cell remyelination after SCI was probably related to the regulation of the Nrg1/ErbB pathway. It is, therefore, possible to suggest that metformin may be a potential therapy for SCI.

Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor.

Neurofibromatosis type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes more than 50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall downregulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-ß1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-ß1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA sequencing, we found that immune cells including macrophages and T cells produce TGF-ß1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-ß1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as biomarkers for disease diagnosis and treatment response.

Inhibitory effect of parthenolide on peripheral nerve degeneration.

Traumatic axonal damage disrupts connections between neurons, leading to the loss of motor and sensory functions. Although damaged peripheral nerves can regenerate, recovery depends on the variety and severity of nerve damage. Thus, many phytochemicals have been studied for their ability to reduce peripheral nerve degeneration, and among them, Parthenolide (PTL), which is extracted from Feverfew has effects against production of free radicals, inflammation, and apoptosis. Thus, we conducted a study to investigate whether PTL has an inhibitory effect on peripheral nerve degeneration during peripheral nerve damage. To verify the effect of PTL on peripheral nerve degeneration process, a morphological comparison of peripheral nerves with and without PTL was performed. PTL significantly reduced the quantity of fragmented ovoid formations at 3DIV (days in vitro). Immunostaining for MBP revealed that the ratio of intact myelin sheaths increased significantly in sciatic nerve with PTL compared with absence of PTL at 3DIV. Furthermore, nerve fibers in the presence of PTL maintained the continuity of Neurofilament (NF) compared to those without at 3DIV. Immunostaining for LAMP1 and p75 NTR showed that the expression of LAMP1 and p75 NTR decreased in the nerve after PTL addition at 3DIV. Lastly, immunostaining for anti-Ki67 revealed that PTL inhibited Ki67 expression at 3DIV compared to without PTL. These results confirm that PTL inhibits peripheral nerve degenerative processes. PTL may be a good applicant to inhibit peripheral nerve degeneration. Our study examined the effect of Parthenolide in preventing degeneration of peripheral nerves by inhibiting the breakdown of peripheral axons and myelin, also inhibiting Schwann cell trans-dedifferentiation and proliferation.

Schwann cells and myelin in human peripheral nerve: Major protein components vary with age, axon size and pathology.

AIMS: We examined major protein components of Schwann cells (SCs) and myelin in normal and diseased human peripheral nerves. METHODS: We evaluated distributions of neural cell adhesion molecule (NCAM), P0 protein (P0) and myelin basic protein (MBP) in frozen sections of 98 sural nerves. RESULTS: Non-myelinating SC in normal adults contained NCAM, but not P0 or MBP. With chronic axon loss, SC without associated axons (Büngner band cells) often co-stained for both NCAM and P0. Onion bulb cells also co-stained for both P0 and NCAM. Infants had many SC with MBP but no P0. All myelin sheaths contained P0. Myelin around large, and some intermediate-sized, axons co-stained for both MBP and P0. Myelin on other intermediate-sized axons had P0, but no MBP. Regenerated axons often had sheaths with MBP, P0 and some NCAM. During active axon degeneration, myelin ovoids often co-stained for MBP, P0 and NCAM. Demyelinating neuropathy patterns included SC (NCAM) loss, and myelin with abnormally distributed, or reduced, P0. CONCLUSIONS: Peripheral nerve SC and myelin have varied molecular phenotypes, related to age, axon size and nerve pathology. In normal adult peripheral nerve, myelin has two different patterns of molecular composition. MBP is mostly absent from myelin around a population of intermediate-sized axons, whereas P0 is present in myelin around all axons. Denervated SCs have a molecular signature that differs from normal SC types. With acute denervation, SCs may stain for both NCAM and MBP. Chronically denervated SCs often stain for both NCAM and P0.