Search Results (111)

In recent years, a long list of relevant studies has highlighted the engagement of the nervous system in the fine-tuning of tumor development and progression. Several authors have shown that different types of nerve fibres (sympathetic, parasympathetic/vagal or somatosensory fibres) may contribute to tumor innervation affecting cancer initiation, progression and metastasis. A large presence of nerve fibres is frequently observed in tumors with respect to the corresponding healthy tissues. In this regard, it is worth noting that in some cases a reduced innervation may associate with slow tumor growth in a tissue-specific manner. Current studies have begun to shed light over the role played in this specific process by Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system. SCs observed in cancer tissues share strong similarities with repair SCs that appear after nerve injury. A large body of research indicates that SCs may have a role in shaping the microenvironment of tumors by regulating the immune response and influencing their invasiveness. In this review, we summarize data relevant to the role of peripheral innervation in general, and of SCs in particular, in defining the progression of different tumors: melanoma that originate in the skin with mainly sensory innervation; pancreatic and liver-derived tumors (e.g., pancreatic adenocarcinoma and cholangiocarcinoma) with mainly autonomous innervation. We conclude by summarizing data regarding hepatocarcinoma (with anatomical predominance of small autonomic nerve fibres) in which the potential relationship between innervation and tumor progression has been little explored, and largely remains to be defined. Full article

Adhesion between Schwann cells (SCs, a type of glial cell in the peripheral nervous system) and their underlying substrates is a fundamental process that holds critical importance for the proper functioning of the peripheral nervous system. Conducting further in-depth research into the adhesion mechanisms of nerve cells is of paramount significance, as it can pave the way for the development of highly effective biomaterials and facilitate the repair of nerve injuries. Thyroid Receptor Interaction Protein 6 (TRIP6), a member of the ZYXIN family of LIM domain-containing proteins, serves as a key component of focal adhesions. It plays a pivotal role in regulating a diverse array of cellular responses, including the reorganization of the actin cytoskeleton and cell adhesion. Accumulated data indicate that RSC96 cells (rat Schwann cells), which are rat Schwann cells, exhibit integrin-based mechanosensitivity during the initial phase of adhesion, specifically within the first 24 h. This enables the cells to sense and respond to alterations in matrix stiffness. The results of immunofluorescence staining experiments revealed intriguing findings. An increase in matrix stiffness not only led to significant changes in the morphological parameters of RSC96 ells, such as circularity, aspect ratio, and cell spreading area, but also enhanced the expression levels of TRIP6, focal adhesion kinase (FAK), and vinculin within these cells. These changes collectively promoted the adhesion of RSC96 cells to the matrix. Furthermore, when TRIP6 expression was silenced in RSC96 cells cultured on hydrogels, a notable decrease in the expression of both FAK and vinculin was observed. This, in turn, had a detrimental impact on cell adhesion. In summary, the present study strongly suggests that TRIP6 may play a crucial role in promoting the adhesion of RSC96 cells to polyacrylamide hydrogels with varying stiffness. This research not only offers a fresh perspective on the study of the integrin-mediated force regulation of cell adhesion but also lays a solid foundation for potential applications in tissue engineering, regenerative medicine, and other related fields. Full article

Laser-generated structures have a huge potential to induce an alignment of biological cells, which may be important for various fields in medicine and biotechnology. We describe the formation of fs-laser-induced micro- and nanostructures for achieving the directed growth of Schwann cells, a type of glial cell that can support the regeneration of nerve pathways by guiding the neuronal axons in the direction of their alignment. Polymer surfaces, i.e., polycarbonate (PC) or cellulose acetate butyrate (CAB), were exposed to the beam of a 1040 nm Yb-based amplified fs-laser system with a pulse length of about 350 fs. With appropriate parameters, the laser exposure resulted in a surface topography with oriented micro-grooves, which, for PC, were covered with nano-ripples. Schwann cell growth on these substrates was inspected after 3 to 5 days of cultivation by means of scanning electron microscopy (SEM). We show that Schwann cells can grow in a certain direction, predetermined by micro-groove or nano-ripple orientation. In contrast, cells cultivated on randomly oriented nanofibers or unstructured surfaces show an omnidirectional growth behavior. This method may be used in the future to produce nerve conduits for the treatment of injuries to the peripheral nervous system. Full article

Peripheral nervous system (PNS) neurons, including motor neurons (MNs), possess a remarkable ability to regenerate and reinnervate target muscles following nerve injury. This process is orchestrated by a combination of intrinsic neuronal properties and extrinsic factors, with Schwann cells (SCs) playing a central role. Upon injury, SCs transition into a repair phenotype that allows axonal regeneration through molecular signaling and structural guidance. However, the identity of the SCs’ reprogramming factors is only partially known. We previously identified hydrogen peroxide (H₂O₂) as an early and key driver of nerve repair, inducing gene expression rewiring in SCs to support nerve re-growth. In this study, we quantitatively assessed the role of H₂O₂ in the activation of key pro-regenerative signaling pathways in SCs following sciatic nerve compression, specifically the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun, which are essential for functional nerve recovery. Notably, we found that H₂O₂ neutralization does not impact degeneration, but it significantly affects the regenerative response. Collectively, our findings establish H₂O₂ as a promising regulator of the Schwann cell injury response at the injury site, linking oxidative signaling to the molecular mechanisms governing nerve regeneration. Full article

This study investigated the mechanism underlying Paeonol’s therapeutic efficacy against neuropathic pain. GSE158892 dataset data were used to conduct a scRNA-seq analysis. In cell experiments, Schwann cells and macrophages were utilized to examine pain pathogenesis using specific inhibitors. Thirty-two SD rats were randomly divided into four groups: sham, chronic constriction injury (CCI), ibuprofen, and Paeonol. Behavioral tests combined with ELISA, PCR, western blot, immunohistochemistry, and immunofluorescence analyses were conducted. CellChat analysis demonstrated that, following peripheral nerve injury, Schwann cells secreted IL-34, which interacted with CSF1R on macrophages, leading to the infiltration and activation of macrophages. Paeonol reduced IL-34 production by Schwann cells induced with LPS. Conditioned medium from LPS-stimulated Schwann cells treated with Paeonol did not cause macrophage proliferation or migration, activation of the CSF1 pathway, or ROS production. In CCI rats, Paeonol alleviated mechanical and cold hyperalgesia, while reducing the production of serum inflammatory mediators. Additionally, Paeonol decreased the expression levels of IL-34, CSF1R, phosphorylated ERK (p-ERK), phosphorylated NF-κB (p-NF-κB), and components of the NLRP3 inflammasome in the dorsal root ganglia of CCI rats. Conclusion: Alleviation of neuropathic pain by Paeonol treatment may be achieved by inhibiting the IL-34–CSF1R interaction, suppressing Schwann cell–macrophage interactions, and reducing DRG neuroinflammation. Full article

Peripheral nerve injury disrupts the function of the peripheral nervous system, leading to sensory, motor, and autonomic deficits. While peripheral nerves possess an intrinsic regenerative capacity, complete sensory and motor recovery remains challenging due to the unpredictable nature of the healing process, which is influenced by the extent of the injury, age, and timely intervention. Recent advances in microsurgical techniques, imaging technologies, and a deeper understanding of nerve microanatomy have enhanced functional outcomes in nerve repair. Nerve injury initiates complex pathophysiological responses, including Wallerian degeneration, macrophage activation, Schwann cell dedifferentiation, and axonal sprouting. Complete nerve disruptions require surgical intervention to restore nerve continuity and function. Direct nerve repair is the gold standard for clean transections with minimal nerve gaps. However, in cases with larger nerve gaps or when direct repair is not feasible, alternatives such as autologous nerve grafting, vascularized nerve grafts, nerve conduits, allografts, and nerve transfers may be employed. Autologous nerve grafts provide excellent biocompatibility but are limited by donor site morbidity and availability. Vascularized grafts are used for large nerve gaps and poorly vascularized recipient beds, while nerve conduits serve as a promising solution for smaller gaps. Nerve transfers are utilized when neither direct repair nor grafting is possible, often involving re-routing intact regional nerves to restore function. Nerve conduits play a pivotal role in nerve regeneration by bridging nerve gaps, with significant advancements made in material composition and design. Emerging trends in nerve regeneration include the use of 3D bioprinting for personalized conduits, gene therapy for targeted growth factor delivery, and nanotechnology for nanofiber-based conduits and stem cell therapy. Advancements in molecular sciences have provided critical insights into the cellular and biochemical mechanisms underlying nerve repair, leading to targeted therapies that enhance axonal regeneration, remyelination, and functional recovery in peripheral nerve injuries. This review explores the current strategies for the therapeutic management of peripheral nerve injuries, highlighting their indications, benefits, and limitations, while emphasizing the need for tailored approaches based on injury severity and patient factors. Full article

Neuroplasticity, the ability of the nervous system to adapt structurally and functionally in response to environmental interactions and injuries, is a cornerstone of recovery in the central (CNS) and peripheral nervous systems (PNS). This review explores the mechanisms underlying neuroplasticity, focusing on the dynamic roles of cellular and molecular processes in recovery from nervous system injuries. Key cellular players, including Schwann cells, oligodendrocytes, and neural stem cells, are highlighted for their contributions to nerve repair, myelination, and regeneration. Advances in therapeutic interventions, such as electrical stimulation, bioluminescent optogenetics, and innovative nerve grafting techniques, are discussed alongside their potential to enhance recovery and functional outcomes. The molecular underpinnings of plasticity, involving synaptic remodeling, homeostatic mechanisms, and activity-dependent regulation of gene expression, are elucidated to illustrate their role in learning, memory, and injury repair. Integrating emerging technologies and therapeutic approaches with a foundational understanding of neuroplasticity offers a pathway toward more effective strategies for restoring nervous system functionality after injury. Full article

Pathological changes and the cellular and molecular mechanisms underlying axonopathy and myelinopathy are key to understanding a wide range of inherited and acquired peripheral nerve disorders. While the clinical indications for nerve biopsy have diminished over time, its diagnostic value remains significant in select conditions, offering a unique window into the pathophysiological processes of peripheral neuropathies. Evidence highlights the symbiotic relationship between axons and myelinating Schwann cells, wherein disruptions in axo-glial interactions contribute to neuropathogenesis. This review synthesizes recent insights into the pathological and molecular underpinnings of axonopathy and myelinopathy. Axonopathy encompasses Wallerian degeneration, axonal atrophy, and dystrophy. Although extensively studied in traumatic nerve injury, the mechanisms of axonal degeneration and Schwann cell-mediated repair are increasingly recognized as pivotal in non-traumatic disorders, including dying-back neuropathies. We briefly outline key transcription factors, signaling pathways, and epigenetic changes driving axonal regeneration. For myelinopathy, we discuss primary segmental demyelination and dysmyelination, characterized by defective myelin development. We describe paranodal demyelination in light of recent findings in nodopathies, emphasizing that it is not an exclusive indicator of demyelinating disorders. This comprehensive review provides a framework to enhance our understanding of peripheral nerve pathology and its implications for developing targeted therapies. Full article

Peripheral nerve injury (PNI) remains a significant clinical challenge, often leading to long-term functional impairment. Despite advances in therapies, current repair strategies offer unsatisfactory clinical outcomes. Exosomes derived from induced pluripotent stem cells (iPSC-Exos) have emerged as a promising therapeutic approach in regenerative medicine. This study assesses the efficacy and safety of iPSC-Exos in a rat model of sciatic nerve crush injury. Briefly, iPSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors using Sendai virus vectors and validated for pluripotency. iPSC-Exos were characterized and injected at the injury site. Functional recovery was assessed through gait analysis, grip strength, and pain response. Histological and molecular analyses were used to examine axonal regeneration, myelination, Schwann cell (SC) activation, angiogenesis, and changes in gene expression. iPSC-Exos were efficiently internalized by SC, promoting their proliferation. No adverse effects were observed between groups on body weight, organ histology, or hematological parameters. iPSC-Exos injection significantly enhanced nerve regeneration, muscle preservation, and vascularization, with RNA sequencing revealing activation of PI3K-AKT and focal adhesion pathways. These findings support iPSC-Exos as a safe and effective non-cell-based therapy for PNIs, highlighting their potential for clinical applications in regenerative medicine. Full article

The regenerative potential of mesenchymal stem cell (MSC) secretomes in peripheral nerve injuries warrants rigorous evaluation. This systematic review analyzes their effectiveness in preclinical models of neurotmesis, a complete transection of a nerve. Neurophysiological recovery was assessed through nerve conduction velocity (NCV), a measure of the speed at which electrical impulses travel along a nerve. Following PRISMA guidelines, a systematic search was conducted in PubMed, Scopus, Web of Science, and ScienceDirect (last search July 2024). From 640 initially identified studies, 13 met inclusion criteria, encompassing 514 animals (rats). experimental designs published since 2014 in English or Spanish, focusing on MSC secretomes for nerve regeneration. Exclusion criteria included reviews, case reports, and incomplete data. The risk of bias was assessed using Joanna Briggs Institute tools. Results were synthesized narratively, focusing on functional and structural outcomes. The included studies employed various MSC sources, including adipose tissue, olfactory mucosa, and umbilical cord. Nine studies reported enhanced SFI, favoring secretome-treated groups over controls (mean difference +20.5%, p < 0.01). Seven studies documented increased NCV, with up to 35% higher conduction velocities in treated groups (p < 0.05). Histological outcomes reported in 12 studies showed increased axonal diameter (+25%, p < 0.01), myelin sheath thickness (+30%, p < 0.05), and Schwann cell proliferation. Limitations of the included evidence include methodological heterogeneity and variability in outcome measurement tools. MSC-derived secretomes demonstrate potential as advanced therapeutic strategies for nerve injuries. Personalized approaches considering injury type and clinical context are essential for optimizing outcomes. Full article

Peripheral neuropathy (PN) is a prevalent condition characterized by damage to peripheral nerves, often linked to risk factors such as diabetes. This condition results from various forms of neural damage, including injury to the cell body, axons, or demyelination, frequently beginning with small and thinly or unmyelinated fibers. Such nerve damage disrupts normal signaling, leading to symptoms like numbness, tingling, and pain. Effective nerve repair and regeneration, particularly through remyelination, are essential therapeutic objectives. While vitamin B12’s role in repair processes has been well established, emerging evidence suggests that other neurotropic vitamins, specifically B1 and B6, also contribute significantly to nerve health and symptom relief in PN. In this study, we demonstrate that a combination treatment of vitamins B1, B6, and B12 enhances repair and oxidative stress responses in co-cultures of neural and Schwann cells, leading to improved cell maturation and connectivity compared to vitamin B12 alone. Furthermore, proteomic analysis supports these observations at the molecular level, with enhanced cellular recycling processes like proteasome enhancement, as well as protein synthesis upregulation, needed to rebuild nerve connections and combatting oxidative stress. Our combined morphological and molecular results highlight the potential therapeutic advantage of the B1, B6, and B12 combination over vitamin B12 alone. Full article

Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, characterized by progressive nerve damage driven by chronic hyperglycemia and systemic inflammation. The pathophysiology of DPN is significantly influenced by pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These cytokines promote oxidative stress, vascular dysfunction, and neuronal degeneration by activating important signaling pathways including NF-κB and MAPK. While IL-6 promotes a pro-inflammatory microenvironment, increasing neuronal damage and neuropathic pain, TNF-α and IL-1β worsen Schwann cell failure by compromising axonal support and causing demyelination. Immune cell infiltration and TLR activation increase the inflammatory cascade in DPN, resulting in a persistent neuroinflammatory state that sustains peripheral nerve injury. The main characteristics of DPN are axonal degeneration, decreased neurotrophic support, and Schwann cell dysfunction, which weaken nerve transmission and increase susceptibility to damage. Advanced glycation end-products, TNF-α, and CXCL10 are examples of biomarkers that may be used for early diagnosis and disease progression monitoring. Additionally, crucial molecular targets have been found using proteomic and transcriptome techniques, enabling precision medicine for the treatment of DPN. This review emphasizes the importance of cytokine signaling in the pathogenesis of DPN and how cytokine-targeted treatments might reduce inflammation, restore nerve function, and improve clinical outcomes for diabetic patients. Full article

In general, the nerve cells of the peripheral nervous system regenerate normally within a certain period after the physical damage of their axon. However, when peripheral nerves are transected by trauma or tissue extraction for cancer treatment, spontaneous nerve regeneration cannot occur. Therefore, it is necessary to perform microsurgery to connect the transected nerve directly or insert a nerve conduit to connect it. In this study, we applied human tonsillar mesenchymal stem cell (TMSC)-derived Schwann cell-like cells (TMSC-SCs) to facilitate nerve regeneration and prevent muscle atrophy after neurorrhaphy. The TMSC-SCs were manufactured in a good manufacturing practice facility and termed neuronal regeneration-promoting cells (NRPCs). A rat model of peripheral nerve injury (PNI) was generated and a mixture of NRPCs and fibrin glue was transplanted into the injured nerve after neurorrhaphy. The application of NRPCs and fibrin glue led to the efficient induction of sciatic nerve regeneration, with the sparing of gastrocnemius muscles and neuromuscular junctions. This sparing effect of NRPCs toward neuromuscular junctions might prevent muscle atrophy after neurorrhaphy. These results suggest that a mixture of NRPCs and fibrin glue may be a therapeutic candidate to enable peripheral nerve and muscle regeneration in the context of neurorrhaphy in patients with PNI. Full article

Tau is a microtubule-associated protein that plays a vital role in the mammalian nervous system. Alternative splicing of the MAPT gene leads to the formation of tau isoforms with varying N-terminal inserts and microtubule-binding repeats. Dysregulation of tau alternative splicing has been linked to diseases in the central nervous system, but the roles of tau isoforms in the peripheral nervous system remain unclear. Here, we investigated the alternative splicing of tau exons 4A and 10 in the sciatic nerve and Schwann cells during development and following injury. We discovered that low-molecular-weight (LMW) tau, resulting from the exclusion of exon 4A, and 3R tau, generated by the exclusion of exon 10, diminishes with aging in rat sciatic nerve and Schwann cells. High-molecular-weight (HMW) tau and 3R tau increase in the adult sciatic nerve post-injury. We constructed viruses that expressed HMW−4R, LMW−4R, HMW−3R, and LMW−3R and introduced them into cultured cells or the distal part of the injured sciatic nerve to assess their effects on Schwann cell migration and proliferation. We also examined the effects of the four isoforms on axon growth and debris clearance after sciatic nerve injury. Our results demonstrated that tau isoforms inhibit Schwann cell proliferation while promoting Schwann cell migration and sciatic nerve regeneration. Specifically, the 3R−tau isoforms were more effective than the 4R−tau isoforms in promoting nerve regeneration. In conclusion, our study reveals the roles of tau isoforms in the peripheral nervous system and provides insights into the development of new therapeutic strategies for peripheral nerve injuries. Full article

Background: Schwann cells (SCs) and their plasticity contribute to the peripheral nervous system’s capacity for nerve regeneration after injury. The Egr2/Krox20 promoter antisense RNA (Egr2-AS) recruits chromatin remodeling complexes to inhibit Egr2 transcription following peripheral nerve injury. Methods: RNA-seq and ATAC-seq were performed on control cells, Lenti-GFP-transduced cells, and cells overexpressing Egr2-AS (Lenti-AS). Egr2 AS-RNA was cloned into the pLVX-DsRed-Express2-N1 lentiviral expression vector (Clontech, Mountain View, CA, USA), and the levels of AS-RNA expression were determined. Ezh2 and Wdr5 were immunoprecipitated from rat SCs and RT-qPCR was performed against AS-Egr2 RNA. ChIP followed by DNA purification columns was used to perform qPCR for relevant promoters. Hi-C, HiC-DC+, R, Bioconductor, and TOBIAS were used for significant and differential loop analysis, identifications of COREs and CORE-promotor loops, comparisons of TF activity at promoter sites, and identification of site-specific TF footprints. OnTAD was used to detect TADs, and Juicer was used to identify A/B compartments. Results: Here we show that a Neuregulin-ErbB2/3 signaling axis mediates binding of the Egr2-AS to YY1^Ser184 and regulates its expression. Egr2-AS modulates the chromatin accessibility of Schwann cells and interacts with two distinct histone modification complexes. It binds to EZH2 and WDR5 and enables targeting of H3K27me3 and H3K4me3 to promoters of Egr2 and C-JUN, respectively. Expression of the Egr2-AS results in reorganization of the global chromatin landscape and quantitative changes in the loop formation and contact frequency at domain boundaries exhibiting enrichment for AP-1 genes. In addition, the Egr2-AS induces changes in the hierarchical TADs and increases transcription factor binding scores on an inter-TAD loop between a super-enhancer regulatory hub and the promoter of mTOR. Conclusions: Our results show that Neuregulin-ErbB2/3-YY1 regulates the expression of Egr2-AS, which mediates remodeling of the chromatin landscape in Schwann cells. Full article