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International Journal of Molecular... May 2024The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire...
The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire Schwann cell lineage. While its importance in peripheral myelination is well established, little is known about its role in the early stages of Schwann cell development. In a search for direct target genes of Sox10 in Schwann cell precursors, the transcriptional co-repressor Tle4 was identified. At least two regions upstream of the gene appear involved in mediating the Sox10-dependent activation. Once induced, Tle4 works in tandem with the bHLH transcriptional repressor Hes1 and exerts a dual inhibitory effect on Sox10 by preventing the Sox10 protein from transcriptionally activating maturation genes and by suppressing Sox10 expression through known enhancers of the gene. This mechanism establishes a regulatory barrier that prevents premature activation of factors involved in differentiation and myelin formation by Sox10 in immature Schwann cells. The identification of Tle4 as a critical downstream target of Sox10 sheds light on the gene regulatory network in the early phases of Schwann cell development. It unravels an elaborate regulatory circuitry that fine-tunes the timing and extent of Schwann cell differentiation and myelin gene expression.
Topics: Schwann Cells; SOXE Transcription Factors; Cell Differentiation; Animals; Co-Repressor Proteins; Rats; Mice; Feedback, Physiological; Myelin Sheath; Gene Expression Regulation; Humans; Transcription Factor HES-1
PubMed: 38791273
DOI: 10.3390/ijms25105234 -
Journal of Nanobiotechnology May 2024Endothelial cell (EC)-driven intraneural revascularization (INRV) and Schwann cells-derived exosomes (SCs-Exos) both play crucial roles in peripheral nerve injury (PNI)....
BACKGROUND
Endothelial cell (EC)-driven intraneural revascularization (INRV) and Schwann cells-derived exosomes (SCs-Exos) both play crucial roles in peripheral nerve injury (PNI). However, the interplay between them remains unclear. We aimed to elucidate the effects and underlying mechanisms of SCs-Exos on INRV following PNI.
RESULTS
We found that GW4869 inhibited INRV, as well as that normoxic SCs-Exos (N-SCs-Exos) exhibited significant pro-INRV effects in vivo and in vitro that were potentiated by hypoxic SCs-Exos (H-SCs-Exos). Upregulation of glycolysis emerged as a pivotal factor for INRV after PNI, as evidenced by the observation that 3PO administration, a glycolytic inhibitor, inhibited the INRV process in vivo and in vitro. H-SCs-Exos more significantly enhanced extracellular acidification rate/oxygen consumption rate ratio, lactate production, and glycolytic gene expression while simultaneously suppressing acetyl-CoA production and pyruvate dehydrogenase E1 subunit alpha (PDH-E1α) expression than N-SCs-Exos both in vivo and in vitro. Furthermore, we determined that H-SCs-Exos were more enriched with miR-21-5p than N-SCs-Exos. Knockdown of miR-21-5p significantly attenuated the pro-glycolysis and pro-INRV effects of H-SCs-Exos. Mechanistically, miR-21-5p orchestrated EC metabolism in favor of glycolysis by targeting von Hippel-Lindau/hypoxia-inducible factor-1α and PDH-E1α, thereby enhancing hypoxia-inducible factor-1α-mediated glycolysis and inhibiting PDH-E1α-mediated oxidative phosphorylation.
CONCLUSION
This study unveiled a novel intrinsic mechanism of pro-INRV after PNI, providing a promising therapeutic target for post-injury peripheral nerve regeneration and repair.
Topics: Schwann Cells; Exosomes; Animals; Glycolysis; Endothelial Cells; Mice; Peripheral Nerve Injuries; Male; Rats; MicroRNAs; Mice, Inbred C57BL; Neovascularization, Physiologic; Rats, Sprague-Dawley; Aniline Compounds; Benzylidene Compounds
PubMed: 38789980
DOI: 10.1186/s12951-024-02536-y -
The Journal of Headache and Pain May 2024The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER...
The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand galectin-3 has been found to be elevated in serum of migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and galectin-3 expression in rat trigeminal ganglia. RT-qPCR was used to assess MERTK gene expression in blood, and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache compared to controls. In addition, MERTK ligand galectin-3 was found at increased concentration in the serum of study participants with cluster headache, whereas the levels of MERTK ligands growth arrest specific 6 and protein S unaffected. MERTK and galectin-3 were both expressed in rat trigeminal ganglia. Galectin-3 was primarily localized in smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and galectin-3 in tissue from study participants with cluster headache, as well as the presence of MERTK in rat peripheral satellite glia cells and Schwann cells in the trigeminal ganglia, further highlights MERTK signalling as an interesting potential future therapeutic target in primary headache.
Topics: Animals; Cluster Headache; c-Mer Tyrosine Kinase; Trigeminal Ganglion; Humans; Male; Rats; Female; Proto-Oncogene Mas; Adult; Middle Aged; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases; Blood Proteins; Galectins
PubMed: 38783191
DOI: 10.1186/s10194-024-01791-6 -
Radiology Case Reports Aug 2024Schwannomas are slow growing, benign tumours arising from Schwann cells. They are usually solitary and are sometimes associated with Neurofibromatosis type 1 and 2. As...
Schwannomas are slow growing, benign tumours arising from Schwann cells. They are usually solitary and are sometimes associated with Neurofibromatosis type 1 and 2. As reported by Okada et al., while approximately 25%-40% of extra-cranial schwannomas occur in the head and neck region, Schwannomas of the oral cavity are very uncommon, accounting for only 1% of all Schwannomas. We report a case of a sublingual schwannoma in a 47-year-old female, discovered incidentally during the workup for tinnitus. The radiological and histopathological findings, along with a literature review, are presented.
PubMed: 38779191
DOI: 10.1016/j.radcr.2024.04.038 -
Biomedicine & Pharmacotherapy =... Jun 2024Pro-inflammatory macrophages (M1-polarized) play a crucial role in neuroinflammation and neuropathic pain following nerve injury. Redirecting macrophage polarization...
Pro-inflammatory macrophages (M1-polarized) play a crucial role in neuroinflammation and neuropathic pain following nerve injury. Redirecting macrophage polarization toward anti-inflammatory (M2-polarized) phenotypes offers a promising therapeutic strategy. Recognized for their anti-inflammatory and immunomodulatory properties, probiotics are becoming a focal point of research. This study investigated the effects of Lactobacillus plantarum on macrophage polarization, nerve protection, and neuropathic pain behavior following chronic constriction injury (CCI) of the median nerve. Rats received daily oral doses of L. plantarum for 28 days before and 14 days after CCI. Subsequently, behavioral and electrophysiological assessments were performed. The M1 marker CD86 levels, M2 marker CD206 levels, and concentrations of pro-inflammatory and anti-inflammatory cytokines in the injured median nerve were assessed. L. plantarum administration effectively reduced neuropathic pain behavior and the Firmicutes to Bacteroidetes ratio after CCI. Moreover, L. plantarum treatment increased serum short-chain fatty acids (SCFAs) levels, preserved myelination of the injured median nerve, and suppressed injury-induced discharges. In CCI rats treated with L. plantarum, there was a reduction in CD86 and pro-inflammatory cytokine levels, accompanied by an increase in CD206 and the release of anti-inflammatory cytokines. Furthermore, receptors for anti-inflammatory cytokines were localized on Schwann cells, and their expression was significantly upregulated in the injured nerves of CCI rats receiving L. plantarum. In conclusion, L. plantarum shifts macrophage phenotypes from M1 to M2 by promoting the production of SCFAs and enhancing the release of anti-inflammatory cytokines. Ultimately, this process preserves nerve fiber integrity and impedes the onset of neuropathic pain.
Topics: Animals; Neuralgia; Macrophages; Male; Disease Models, Animal; Lactobacillus plantarum; Rats; Probiotics; Cytokines; Behavior, Animal; Peripheral Nervous System Diseases; Rats, Wistar; Cell Polarity
PubMed: 38776678
DOI: 10.1016/j.biopha.2024.116769 -
Cell Death & Disease May 2024Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe...
Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.
Topics: Animals; GTP-Binding Protein gamma Subunits; Cell Differentiation; Mice; Oligodendrocyte Precursor Cells; Myelin Sheath; Cognitive Dysfunction; Lipid Metabolism; Oligodendroglia; Mice, Inbred C57BL; PPAR gamma; Mice, Knockout; Male; Rosiglitazone
PubMed: 38773070
DOI: 10.1038/s41419-024-06737-z -
IScience Jun 2024Establishing robust models of human myelinating Schwann cells is critical for studying peripheral nerve injury and disease. Stem cell differentiation has emerged as a...
Establishing robust models of human myelinating Schwann cells is critical for studying peripheral nerve injury and disease. Stem cell differentiation has emerged as a key human cell model and disease motivating development of Schwann cell differentiation protocols. Human embryonic stem cells (hESCs) are considered the ideal pluripotent cell but ethical concerns regarding their use have propelled the popularity of human induced pluripotent stem cells (hiPSCs). Given that the equivalence of hESCs and hiPSCs remains controversial, we sought to compare the molecular and functional equivalence of hESC- and hiPSC-derived Schwann cells generated with our previously reported protocol. We identified only modest transcriptome differences by RNA sequencing and insignificant proteome differences by antibody array. Additionally, both cell types comparably improved nerve regeneration and function in a chronic denervation and regeneration animal model. Our findings demonstrate that Schwann cells derived from hESCs and hiPSCs with our protocol are molecularly comparable and functionally equivalent.
PubMed: 38770143
DOI: 10.1016/j.isci.2024.109855 -
Neural Regeneration Research Jan 2025JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as...
JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.
PubMed: 38767492
DOI: 10.4103/1673-5374.390956 -
Laryngoscope Investigative... Jun 2024Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an...
OBJECTIVES
Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity.
METHODS
RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay.
RESULTS
The LC dose of cisplatin was determined to be 3.76 μM ( = 2.2 x 10). When co-dosed with cisplatin and a therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone.
CONCLUSION
RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity.
LEVEL OF EVIDENCE
N/A Laryngoscope, 2023.
PubMed: 38765675
DOI: 10.1002/lio2.1256 -
Skeletal Muscle May 2024Loss-of-function mutations in MEGF10 lead to a rare and understudied neuromuscular disorder known as MEGF10-related myopathy. There are no treatments for the progressive...
Loss-of-function mutations in MEGF10 lead to a rare and understudied neuromuscular disorder known as MEGF10-related myopathy. There are no treatments for the progressive respiratory distress, motor impairment, and structural abnormalities in muscles caused by the loss of MEGF10 function. In this study, we deployed cellular and molecular assays to obtain additional insights about MEGF10-related myopathy in juvenile, young adult, and middle-aged Megf10 knockout (KO) mice. We found fewer muscle fibers in juvenile and adult Megf10 KO mice, supporting published studies that MEGF10 regulates myogenesis by affecting satellite cell differentiation. Interestingly, muscle fibers do not exhibit morphological hallmarks of atrophy in either young adult or middle-aged Megf10 KO mice. We next examined the neuromuscular junction (NMJ), in which MEGF10 has been shown to concentrate postnatally, using light and electron microscopy. We found early and progressive degenerative features at the NMJs of Megf10 KO mice that include increased postsynaptic fragmentation and presynaptic regions not apposed by postsynaptic nicotinic acetylcholine receptors. We also found perisynaptic Schwann cells intruding into the NMJ synaptic cleft. These findings strongly suggest that the NMJ is a site of postnatal pathology in MEGF10-related myopathy. In support of these cellular observations, RNA-seq analysis revealed genes and pathways associated with myogenesis, skeletal muscle health, and NMJ stability dysregulated in Megf10 KO mice compared to wild-type mice. Altogether, these data provide new and valuable cellular and molecular insights into MEGF10-related myopathy.
Topics: Animals; Neuromuscular Junction; Mice, Knockout; Mice; Disease Models, Animal; Membrane Proteins; Muscular Diseases; Schwann Cells; Muscle, Skeletal; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Male
PubMed: 38760872
DOI: 10.1186/s13395-024-00342-6