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Myelin-forming oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) are essential for structural and functional homeostasis of nervous tissue. Albeit with certain similarities, the regulation of CNS and PNS myelination is executed differently. Recent advances highlight the coordinated regulation of oligodendrocyte myelination by amino-acid sensing and growth factor signaling pathways. In this review, we discuss novel insights into the understanding of differential regulation of oligodendrocyte and Schwann cell biology in CNS and PNS myelination, with particular focus on the roles of growth factor-stimulated RHEB-mTORC1 and GATOR2-mediated amino-acid sensing/signaling pathways. We also discuss recent progress on the metabolic regulation of oligodendrocytes and Schwann cells and the impact of their dysfunction on neuronal function and disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Peripheral nerve injury is a common clinical trauma. At present, the end-to-end anastomosis was commonly used in the treatment of short-distance nerve injury, whereas graft bridging was required in the long-distance nerve injury. Schwann cell-derived exosomes could elevate neuronal survival, improve the regeneration microenvironment, promote axonal regeneration, and have a good application prospect in the field of peripheral nerve injury and repair. OBJECTIVE: To review the research progress of Schwann cell-derived exosomes in repair and regeneration after peripheral nerve injury. METHODS: The relevant articles published from 2000 to 2022 were searched from PubMed, Wanfang, and CNKI databases by computer. The Chinese and English search terms were “Schwann cell, exosomes, vesicles, peripheral nerve, sciatic nerve”. The preliminary searched articles were screened according to the inclusion and exclusion criteria, and a total of 52 articles were included for in-depth analysis. RESULTS AND CONCLUSION: (1) The proliferation and migration of Schwann cells play an important role in the repair and regeneration after peripheral nerve injury. Schwann cells could promote the regeneration and repair of injured peripheral nerves through a variety of signal transduction pathways. (2) Exosomes could mediate intercellular communication by transferring bioactive substances to maintain normal physiological processes, which had a great potential in the treatment of peripheral nervous system damage. (3) Schwann cell-derived exosomes played a role in promoting regeneration and repair of peripheral nerve injury by participating in axon regeneration and growth regulation so as to provide a new therapeutic strategy for peripheral nerve injury. [ABSTRACT FROM AUTHOR]

After peripheral nerve injury, demyelinating Schwann cells discharge myelin debris and macrophages execute myelin degradation, leading to demyelination of degenerating axons, which is essential for efficient nerve regeneration. In this study, we show that vacuolar-type proton ATPase subunit d2 (Atp6v0d2) is among the most highly upregulated genes in degenerating mouse sciatic nerves after nerve injury using microarray analysis. ATP6V0D2 is mostly expressed in macrophages of injured nerves. Atp6v0d2 knockout mice display delayed peripheral nerve demyelination and significantly attenuated myelin lipid digestion after nerve injury. However, macrophage recruitment and Schwann cell dedifferentiation are unaffected by loss of Atp6v0d2 expression. Taken together, these data demonstrate that ATP6V0D2 in macrophages is specifically required for demyelination during Wallerian degeneration. • Atp6v0d2 is highly upregulated in mouse sciatic nerves after nerve injury. • ATP6V0D2 is expressed in macrophages during Wallerian degeneration. • Demyelination and myelin lipid digestion were delayed in Atp6v0d2 knockout mice. • Schwann cell dedifferentiation was unaffected in Atp6v0d2 knockout mice. [ABSTRACT FROM AUTHOR]

Human studies, in combination with animal and cellular models, support glial cells as both major contributors to neurodegenerative diseases and promising therapeutic targets. Among glial cells, oligodendrocytes and Schwann cells are the myelinating glial cells of the central and peripheral nervous system, respectively. In this review, we discuss the contributions of these central and peripheral myelinating glia to the pathomechanisms of polyglutamine (polyQ) spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17. First, we highlight the function of oligodendrocytes in healthy conditions and how they are disrupted in polyQ SCA patients and diseased model systems. We then cover the role of Schwann cells in peripheral nerve function and repair as well as their possible role in peripheral neuropathy in polyQ SCAs. Finally, we discuss potential polyQ SCA therapeutic interventions in myelinating glial. [ABSTRACT FROM AUTHOR]

Background: Schwann cells (SCs) respond to nerve injury by transforming into the repair-related cell phenotype, which can provide the essential signals and spatial cues to promote axonal regeneration and induce target reinnervation. Endothelial cells (ECs) contribute to intraneural angiogenesis contributing to creating a permissive microenvironment. The coordination between ECs and SCs within injury sites is crucial in the regeneration process, however, it still unclear. As the intercellular vital information mediators in the nervous system, exosomes have been proposed to take a significant role in regulating regeneration. Thus, the main purpose of this study is to determine the facilitative effect of ECs-derived exosomes on SCs and to seek the underlying mechanism. Results: In the present study, we collected exosomes from media of ECs. We demonstrated that exosomes derived from ECs possessed the favorable neuronal affinity both in vitro and in vivo. Further research indicated that EC-exosomes (EC-EXO) could boost and maintain repair-related phenotypes of SCs, thereby enhancing axonal regeneration, myelination of regenerated axons and neurologically functional recovery of the injured nerve. MiRNA sequencing in EXO-treated SCs and control SCs indicated that EC-EXO significantly up-regulated expression of miR199-5p. Furthermore, this study demonstrated that EC-EXO drove the conversion of SC phenotypes in a PI3K/AKT/PTEN-dependent manner. Conclusion: In conclusion, our research indicates that the internalization of EC-EXO in SCs can promote nerve regeneration by boosting and maintaining the repair-related phenotypes of SCs. And the mechanism may be relevant to the up-regulated expression of miR199-5p and activation of PI3K/AKT/PTEN signaling pathway. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that Schwann cells’ (SCs) death caused by high glucose (HG) is involved in the pathological process of diabetic peripheral neuropathy (DPN). Ferroptosis is a novel form of regulatory cell death driven by iron-dependent lipid peroxidation. However, it is not clear whether ferroptosis is involved in the death process of SCs induced by HG. The expression of ferroptosis-related indicators in the serum of DPN patients was detected by ELISA. Subsequently, using cell counting kit‑8, western blot, real-time PCR, and Ki-67 staining, we investigated the effects of HG on the ferroptosis of SCs and initially explored the underlying mechanism. The results showed that the serum levels of glutathione peroxidase 4 (GPX4) and glutathione in patients with DPN decreased, while malondialdehyde levels increased significantly. Then, we observed that erastin and HG induced ferroptosis in SCs, resulting in the decrease in cell activity and the expression level of GPX4 and SLC7A11, which could be effectively reversed by the ferroptosis inhibitor Fer-1. Mechanistically, HG induced ferroptosis in SCs by inhibiting the NRF2 signaling pathway. Our results showed that ferroptosis was involved in the death process of SCs induced by HG. Inhibition of ferroptosis in SCs might create a new avenue for the treatment of DPN. [ABSTRACT FROM AUTHOR]

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, in vivo and ex vivo analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs. We show that this model enables the isolation of the SCs with high purity from the skin and multiple other organs. We used this model to study phenotypic and functional reprogramming of the SCs in the skin adjacent to melanoma tumors. Transcriptomic analyses of the peritumoral skin SCs versus skin SCs from tumor-free mice revealed that the former existed in a repair-like state typically activated during nerve and tissue injury. Peritumoral skin SCs also downregulated pro-inflammatory genes and pathways related to protective anti-tumor responses. In vivo and ex vivo functional assays confirmed immunosuppressive activities of the peritumoral skin SCs. Specifically, melanoma-reprogrammed SCs upregulated 12/15-lipoxygenase (12/15-LOX) and cyclooxygenase (COX)-2, and increased production of anti-inflammatory polyunsaturated fatty acid (PUFA) metabolites prostaglandin E2 (PGE2) and lipoxins A4/B4. Inhibition of 12/15-LOX or COX2 in SCs, or EP4 receptor on lymphocytes reversed SC-dependent suppression of anti-tumor T-cell activation. Therefore, SCs within the skin adjacent to melanoma tumors demonstrate functional switching to repair-like immunosuppressive cells with dysregulated lipid oxidation. Our study suggests the involvement of the melanoma-associated repair-like peritumoral SCs in the modulation of locoregional and systemic anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

Introduction: Strategies of Schwann cell (SC) transplantation for regeneration of peripheral nerve injury involve many limitations. Stem cells can be used as alternative cell source for differentiation into Schwann cells. Given the high potential of neural crest-derived stem cells for the generation of multiple cell lineages, in this research, we considered whether olfactory ectomesenchymal stem cells (OE-MSCs) derived from neural crest can spontaneously differentiate into SC lineage Methods: OE-MSCs were isolated from human nasal mucosa and characterized by the mesenchymal and neural crest markers. The cells were cultured in glial growth factors-free medium and further investigated in terms of the phenotypic and functional properties. Results: Immunocytochemical staining and real-time PCR analysis indicated that the cultured OE-MSCs expressed SCs markers, SOX10, p75, S100, GFAP and MBP, differentiation indicative. It was found that the cells could secrete neurotrophic factors, including brainderived neurotrophic factor (BDNF) and nerve growth factor (NGF). Furthermore, after cocultured with PC12, the mean neurite length was enhanced by OE-MSCs. Conclusion: The findings indicated that OE-MSCs could be differentiated spontaneously into SC-like phenotypes, suggesting their applications for transplantation in peripheral nerve injuries. [ABSTRACT FROM AUTHOR]

Inflammation of the dental pulp due to caries is a highly prevalent pathology which causes intense pain. Here, we sought to correlate the clinical picture with the histopathology of the affected tissue. The interaction between nociceptive neurons and immune cells is fundamental to regulate the inflammatory response, but little is known about the glial network involved in this process, and its impact on caries pathogenesis. This study characterized Schwann cells and other neuroimmune components in human dental pulps with reversible and symptomatic irreversible pulpitis (IP). Twenty eight human teeth were extracted for reasons beyond the scope of this study. Twelve were diagnosed as reversible and symptomatic IP respectively, and 4 as controls. The teeth were decalcified, processed for immunolabeling and analyzed with confocal microscopy. Symptomatic IP was characterized by a significantly higher density of neutrophils, and the release of neutrophil extracellular traps. Between IP and healthy controls, there were significant differences in the density of Schwann cells, macrophages, and neutrophils, in addition to morphological alterations. In IP, Schwann cell arborization extended toward the pulpodentinal interface along with more spindle-shaped cell bodies, while some macrophages displayed a distinct fusiform phenotype. The dental pulp has a complex multicellular organization and its pulpodentinal interface acts as a barrier in which Schwann and immune cells are distributed strategically to stop the progress of pathogens. A synergistic interaction of Schwann cells with immune cells creates a novel perspective to better understand the role of these glial cells and their active participation in pulpal inflammation. [ABSTRACT FROM AUTHOR]

Background: Schwann cells (SCs) are specialized glial cells of the peripheral nervous system that produce myelin and promote fast action potential propagation. In order to myelinate, SCs engage in a series of events that include migration and division along axons, followed by extensive cytoskeletal rearrangements that ensure axonal ensheathment and myelination. SCs are polarized and extend their processes along an abaxonal‐adaxonal axis. Here, we investigate the role of the apical polarity proteins, Pals1a, and aPKCλ, in SC behavior during zebrafish development. Results: We analyzed zebrafish nok and has mutants deficient for pals1a and aPKCλ function respectively. Using live imaging, transmission electron microscopy and whole mount immunostaining, we show that SCs can migrate and divide appropriately, exhibit normal radial sorting, express myelin markers and ensheath axons on time in has and nok mutants. Conclusions: Pals1a and aPKCλ are not essential for SC migration, division or myelination in zebrafish. Key Findings: Schwann cells are specialized myelinating cells of the peripheral nervous system.In this paper, we use live imaging, genetic, transmission electron microscopy and whole mount immunostaining to conduct a thorough analysis of the role of the two canonical polarity proteins Pals1 and aPKC in the development of Schwann cells in zebrafish.This study provides evidence that the canonical polarity proteins tested so far are not required for Schwann cell development in zebrafish underscoring strong differences between mice and zebrafish peripheral glial polarity.This strongly suggests, for the first time, that Schwann cell polarity is established differently in zebrafish and that the abaxonal‐adaxonal axis is independent of canonical polarity proteins.This highlights a novel example of how polarity might differ between cells (epithelial vs glial) and species (zebrafish vs mice). [ABSTRACT FROM AUTHOR]

Recombinant humanized collagen (rhCol) was an extracellular matrix (ECM)-inspired biomimetic biomaterial prepared by biosynthesis technology, which was considered non-allergenic and could possibly activate tissue regeneration. The influence of tag sequence on both structures and performances of rhCol type III (rhCol III) was investigated, and the effect of rhCol III on cell behaviors was evaluated and discussed using Schwann cells (SCs) as in vitro model that was critical in the repair process after peripheral nerve injury. The results demonstrated that the introduction of tag sequence would influence both advanced structures and properties of rhCol III, while rhCol III regulated SCs adhesion, spreading, migration and proliferation. Also, both nerve growth factor and brain-derived neurotrophic factor increased when exposed to rhCol III. As the downstream proteins of integrin-mediated cell adhesions, phosphorylation of focal adhesion kinase and expression of vinculin was up-regulated along with the promotion of SCs adhesion and migration. The current findings contributed to a better knowledge of the interactions between rhCol III and SCs, and further offered a theoretical and experimental foundation for the development of rhCol III-based medical devices and clinical management of peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Abstract Background The important contribution of glia to mechanisms of injury and repair of the nervous system is increasingly recognized. In stark contrast to the central nervous system (CNS), the peripheral nervous system (PNS) has a remarkable capacity for regeneration after injury. Schwann cells are recognized as key contributors to PNS regeneration, but the molecular underpinnings of the Schwann cell response to injury and how they interact with the inflammatory response remain incompletely understood. Methods We completed bulk RNA-sequencing of Schwann cells purified acutely using immunopanning from the naïve and injured rodent sciatic nerve at 3, 5, and 7 days post-injury. We used qRT-PCR and in situ hybridization to assess cell purity and probe dataset integrity. Finally, we used bioinformatic analysis to probe Schwann cell-specific injury-induced modulation of cellular pathways. Results Our data confirm Schwann cell purity and validate RNAseq dataset integrity. Bioinformatic analysis identifies discrete modules of genes that follow distinct patterns of regulation in the 1st days after injury and their corresponding molecular pathways. These findings enable improved differentiation of myeloid and glial components of neuroinflammation after peripheral nerve injury and highlight novel molecular aspects of the Schwann cell injury response such as acute downregulation of the AGE/RAGE pathway and of secreted molecules Sparcl1 and Sema5a. Conclusions We provide a helpful resource for further deciphering the Schwann cell injury response and a depth of transcriptional data that can complement the findings of recent single cell sequencing approaches. As more data become available on the response of CNS glia to injury, we anticipate that this dataset will provide a valuable platform for understanding key differences in the PNS and CNS glial responses to injury and for designing approaches to ameliorate CNS regeneration.

Peripheral nerve injury (PNI) induces neuroma formation at the severed nerve stump resulting in impaired nerve regeneration and functional recovery in patients. So far, molecular mechanisms and cell types present in the neuroma impeding on regeneration have only sparsely been analyzed. Herein we compare resected human neuroma tissue with intact donor nerves from the same patient. Neuroma from several post-injury timepoints (1–13 months) were included, thereby allowing for temporal correlation with molecular and cellular processes. We observed reduced axonal area and percentage of myelin producing Schwann cells (SCs) compared to intact nerves. However, total SOX10 positive SC numbers were comparable. Notably, markers for SCs in a repair mode including c-JUN, the low-affinity neurotrophin receptor (NTR) p75, SHH (sonic hedgehog) and SC proliferation (phospho-histone H3) were upregulated in neuroma, suggesting presence of SCs in repair status. In agreement, in neuroma, pro-regenerative markers such as phosphorylated i.e. activated CREB (pCREB), ATF3, GAP43 and SCG10 were upregulated. In addition, neuroma tissue was infiltrated by several types of macrophages. Finally, when taken in culture, neuroma SCs were indistinguishable from controls SCs with regard to proliferation and morphology. However, cultured neuroma SCs retained a different molecular signature from control SCs including increased inflammation and reduced gene expression for differentiation markers such as myelin genes. In summary, human neuroma tissue consists of SCs with a repair status and is infiltrated strongly by several types of macrophages. [Display omitted] • Human neuroma tissue contains Schwann cells expressing repair markers. • Repair markers in Schwann cells persist in neuroma up to 12 months after injury. • Neuroma expresses pro-regenerative markers such as pCREB, ATF3, SCG10 and Gap43. • Neuroma tissue is highly fibrotic and infiltrated by macrophages. • Blood vessels organization is altered in neuroma. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) causes motor and sensory defects, has strong impact on life quality and still has no effective therapy. Glycyrrhizic acid (GA) is one of the most widely used in traditional Chinese prescriptions and as a flavoring additive in the food industry; the aims of the study were to investigate the effects of GA during sciatic nerve regeneration in a mouse model of sciatic nerve crush injury. We established peripheral nerve crush model and investigated the effects of GA. We further studied the potential mechanism of action of GA by Western blotting, fluorescence immunohistochemistry, and PCR analysis. GA improves the sensory and motor functions of crushed nerve by preventing Schwann cell loss, axonal loss and promoting remyelination of sciatic nerve. Affected by GA, the inflammatory response in the distal part of the sciatic nerve was reduced. Finally, the neuroprotective properties of GA may be regulated by the nuclear factor (NF)‐κB pathway. Our data suggest that GA can effectively alleviate PNI, and the mechanism involves mediating inflammatory response by suppressing NF-κB pathway activation. Thus, GA may represent a potential therapeutic intervention for nerve crush injury. [ABSTRACT FROM AUTHOR]

Peripheral sensory nerves play critical roles in bone homeostasis and in repair of damaged bone. However, bone defects are generally accompanied by loss of ossification-promoting nerve endings. The cellular networks that connect bone and nerve regeneration are largely unknown, but an understanding of this cross-talk could enable selective modulation of these signals to promote regeneration of diseased or damaged bone. Here we identify myelinating Schwann cells (mSCs) as an essential microenvironmental component connecting bone and nerve regeneration. We found that mSCs accumulate in the region of bone defects, where they support bone regeneration by mediating regeneration of nerves in the vicinity. Consistently, in vivo depletion of mSCs greatly dampened bone regeneration in models of both cranial and femoral bone defects. To exploit this activity of mSCs, we fabricated an aligned self-powered silicon dioxide electret composite membrane (AS), and we showed that the combination of electrical stimulation and aligned topography of fibers on the membrane promoted nerve regeneration by driving myelination of SCs, which subsequently contributed to nerve-dependent bone regeneration. Mechanistically, AS membranes affected myelination of SCs by inhibiting Notch pathway signaling and by driving polarization of macrophages into the anti-inflammatory M2-like phenotype. Our study reveals that mSCs are essential for executing signals between damaged bone and nerves to support generation of both tissues and prompts further studies of biomembranes to stimulate mSCs and support bone regeneration. [Display omitted] • Identifying accumulation of myelinating Schwann cells (mSCs) in the region of bone defects. • Functionally demonstrating that mSCs support both nerve and bone regeneration. • Fabricating self-powered electret membranes (AS) to promote myelination of SCs by inhibiting Notch signaling. • Showing that AS can polarize macrophages into M2-like phenotype to support a microenvironment conducive to tissue repair. • Demonstrating AS membranes promote nerve-dependent bone regeneration in vivo , suggesting clinical potential. [ABSTRACT FROM AUTHOR]

Wallerian degeneration, the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury, is essential for creating a permissive microenvironment for nerve regeneration, and involves cytoskeletal reconstruction. However, it is unclear whether microtubule dynamics play a role in this process. To address this, we treated cultured sciatic nerve explants, an in vitro model of Wallerian degeneration, with the microtubule-targeting agents paclitaxel and nocodazole. We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation, whereas nocodazole-induced microtubule destabilization inhibited these processes. Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration, as well as functional recovery of nerve conduction and target muscle and motor behavior, respectively. These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration. This study was approved by the Animal Care and Use Committee of Southern Medical University, China (approval No. SMU-L2015081) on October 15, 2015.

Wallerian degeneration is a complex biological process that occurs after nerve injury, and involves nerve degeneration and regeneration. Schwann cells play a crucial role in the cellular and molecular events of Wallerian degeneration of the peripheral nervous system. However, Wallerian degeneration regulating nerve injury and repair remains largely unknown, especially the early response. We have previously reported some key regulators of Wallerian degeneration after sciatic nerve injury. Baculoviral inhibitor of apoptosis protein repeat-containing protein 3 (BIRC3) is an important factor that regulates apoptosis-inhibiting protein. In this study, we established rat models of right sciatic nerve injury. In vitro Schwann cell models were also established and subjected to gene transfection to inhibit and overexpress BIRC3. The data indicated that BIRC3 expression was significantly up-regulated after sciatic nerve injury. Both BIRC3 upregulation and downregulation affected the migration, proliferation and apoptosis of Schwan cells and affected the expression of related factors through activating c-fos and ERK signal pathway. Inhibition of BIRC3 delayed early Wallerian degeneration through inhibiting the apoptosis of Schwann cells after sciatic nerve injury. These findings suggest that BIRC3 plays an important role in peripheral nerve injury repair and regeneration. The study was approved by the Institutional Animal Care and Use Committee of Nantong University, China (approval No. 2019-nsfc004) on March 1, 2019.

Proper peripheral myelination depends upon the balance between Schwann cell proliferation and differentiation programs. The serine/threonine kinase mTOR integrates various environmental cues to serve as a central regulator of cell growth, metabolism, and function. We report here that tuberous sclerosis complex 1 (TSC1), a negative regulator of mTOR activity, establishes a stage-dependent program for Schwann cell lineage progression and myelination by controlling cell proliferation and myelin homeostasis. Tsc1 ablation in Schwann cell progenitors in mice resulted in activation of mTOR signaling, and caused over-proliferation of Schwann cells and blocked their differentiation, leading to hypomyelination. Transcriptome profiling analysis revealed that mTOR activation in Tsc1 mutants resulted in upregulation of a polo-like kinase (PLK)-dependent pathway and cell cycle regulators. Attenuation of mTOR or pharmacological inhibition of polo-like kinases partially rescued hypomyelination caused by Tsc1 loss in the developing peripheral nerves. In contrast, deletion of Tsc1 in mature Schwann cells led to redundant and overgrown myelin sheaths in adult mice. Together, our findings indicate stage-specific functions for the TSC1-mTOR-PLK signaling axis in controlling the transition from proliferation to differentiation and myelin homeostasis during Schwann cell development.

Sensory neurons in the PNS demonstrate substantial capacity for regeneration following injury. Recent studies have identified changes in the transcriptome of sensory neurons, which are instrumental for axon regeneration. The role of Schwann cells (SCs) in mediating these changes remains undefined. We tested the hypothesis that SCs regulate expression of genes in sensory neurons before and after PNS injury by comparing mice in which LDL Receptor-related Protein-1 (LRP1) is deleted in SCs (scLRP1-/- mice) with wild-type (scLRP1+/+ ) littermates. LRP1 is an endocytic and cell-signaling receptor that is necessary for normal SC function and the SC response to nerve injury. scLRP1-/- mice represent a characterized model in which the SC response to nerve injury is abnormal. Adult DRG neurons, isolated from scLRP1-/- mice, with or without a conditioning nerve lesion, demonstrated increased neurite outgrowth when cultured ex vivo, compared with neurons from wild-type mice. Following sciatic nerve crush injury, nerve regeneration was accelerated in vivo in scLRP1-/- mice. These results were explained by transcriptional activation of RAGs in DRG neurons in scLRP1-/- mice prior to nerve injury. Although the presence of abnormal SCs in scLRP1-/- mice primed DRG neurons for repair, nerve regeneration in scLRP1-/- mice resulted in abnormalities in ultrastructure, principally in Remak bundles, and with the onset of neuropathic pain. These results demonstrate the importance of SCs in controlling RAG expression by neurons and the potential for this process to cause chronic pain when abnormal. The SC may represent an important target for preventing pain following PNS injury.

Poly(ADP-ribose) (PAR) is a highly negatively charged polymer. PAR is synthesized by poly(ADP-ribose) polymerases (PARPs) and is involved in the assembly and stabilization of macromolecular complexes. Here, the presence and putative roles of poly(ADP-ribosyl)ation (PARylation) associated to adherens junctions (AJ) and the actin cytoskeleton in epithelial and Schwann cells, is reviewed. The hypothesis generated by analogy, stating that PAR is associated to AJ in other cell types, is postulated. According to this hypothesis, PAR associated to puncta adherentia in chemical synapses would participate in plasticity, learning and memory. In turn, PAR associated to fascia adherens in cardiomyocytes, would affect heart beating. PARP inhibitors are currently under development and clinical testing. Basic research in different tissues will probably influence their clinical uses. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is the most common metabolic disease associated with impaired wound healing. Recently, Schwann cells (SCs), the glia of the peripheral nervous system, have been suggested to accelerate normal skin wound healing. However, the roles of SCs in diabetic wound healing are not fully understood. In this study, Full-thickness wounds were made in the dorsal skin of C57/B6 mice and db/db (diabetic) mice. Tissue samples were collected at different time points, and immunohistochemical and immunofluorescence analyses were performed to detect markers of de-differentiated SCs, including myelin basic protein, Sox 10, p75, c-Jun, and Ki67. In addition, in vitro experiments were performed using rat SC (RSC96) and murine fibroblast (L929) cell lines to examine the effects of high glucose conditions (50 mM) on the de-differentiation of SCs and the paracrine effects of SCs on myofibroblast formation. Here, we found that, compared with that in normal mice, wound healing was delayed and SCs failed to rapidly activate a repair program after skin wound injury in diabetic mice. Furthermore, we found that SCs from diabetic mice displayed functional impairments in cell dedifferentiation, cell-cycle re-entry, and cell migration. In vitro, hyperglycemia impaired RSC 96 cell de-differentiation, cell-cycle re-entry, and cell migration, as well as their paracrine effects on myofibroblast formation, including the secretion of TGF-β and Timp1. These results suggest that delayed wound healing in diabetes is due in part to a diminished SC repair response and attenuated paracrine effects on myofibroblast formation. [ABSTRACT FROM AUTHOR]

Titanium and its alloys have been widely used in the field of oral implants over the past few decades. However, the effect of micro-arc oxidation modified titanium surface on Schwann cells has not been studied, which is of great significance for nerve regeneration around implants and improvement of osseoperception. In this study, the characterization of the titanium surface modified by micro-arc oxidation (MAO) was detected by scanning electron microscope (SEM), XPS and a contact angle measurement system. Schwann cells (SCs) were cultured on titanium surfaces of micro-arc oxidation (MAO) and pure titanium (Ti). At different time points, the morphology and adhesion of SCs on the titanium surfaces were observed by SEM. Cell proliferation activity was detected by the CCK-8 method. The expression levels of mRNA and proteins of nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) were detected by RT-PCR, immunofluorescence and western blot. The results of this in vitro study revealed that micro-arc-oxidation-modified titanium surfaces promoted Schwann cell proliferation and secretion of neurotrophic factors compared with pure titanium. CCK-8 results showed that the number of Schwann cells on MAO surfaces was significantly higher than that of the Ti group on day 7. The mRNA expressions of Ngf and Gdnf were up-regulated in both groups from day 1 to day 7. On day 3 and day 7, the gene expression of Ngf in the MAO group was significantly higher than that of the Ti group. On day 7, the MAO group appeared significantly up-regulated in gene expression level of Gdnf. The results of western blot were consistent. Micro-arc oxidation modification provides an accurate and effective method for promoting nerve regeneration of titanium microtopography coatings, which have potential significance for promoting patients' osseoperception ability in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Evidence has shown neurons and glial cells were closely related to tumor progression. As the predominant glial cells in the external innervated nerves of the gastrointestinal, the role of Schwann cells (SCs) in colorectal cancer (CRC) has not been well explored. Methods: HCT-116 andHT-29 CRC cellswere treated with conditionedmedium (CM) from SCs, and the cells' proliferative and migrating capacities were examined. Cytokine array analysis was used to identify the tumor-promotingcytokines from SCs-CM. Molecular changes from SCs after being co-cultured with tumor cells were detected by ELISA and reverse transcription-quantitative PCR. The activation of the nuclear factor kappa B (NF-κB) signaling pathway in SCs was demonstrated by immunofluorescence staining. Neutralizing antibody was used to verify the tumor-promoting effects of key cytokine. Results: Migration and invasion of CRC cells were markedly aided by CM from SCs in vitro. Interleukin-8 (IL-8) was identified as an effective factor. SCs cocultured with CRC cells upregulated IL-8 expression, which may be related to its activated NF-κB signaling pathway. Neutralization of IL-8 attenuated the tumor-promoting effect of SCs. Conclusion: The present study identified a new mechanism of tumorneuroglia interaction, enriching the concept of the tumor-neural axis in the tumor microenvironment of CRC, which also inspired potential targets for anticancer therapies. [ABSTRACT FROM AUTHOR]

After spinal cord transection (SCT) the interaction between motoneurons (MNs) and muscle is impaired, due to reorganization of the spinal network after a loss of supraspinal inputs. Rats subjected to SCT, treated with intraspinal injection of a AAV-BDNF (brain-derived neurotrophic factor) construct, partially regained the ability to walk. The central effects of this treatment have been identified, but its impact at the neuromuscular junction (NMJ) has not been characterized. Here, we compared the ability of NMJ pre- and postsynaptic machinery in the ankle extensor (Sol) and flexor (TA) muscles to respond to intraspinal AAV-BDNF after SCT. The gene expression of cholinergic molecules (VAChT, ChAT, AChE, nAChR, mAChR) was investigated in tracer-identified, microdissected MN perikarya, and in muscle fibers with the use of qPCR. In the NMJs, a distribution of VAChT, nAChR and Schwann cells was studied by immunofluorescence, and of synaptic vesicles and membrane active zones by electron microscopy. We showed partial protection of the Sol NMJs from disintegration, and upregulation of the VAChT and AChE transcripts in the Sol, but not the TA MNs after spinal enrichment with BDNF. We propose that the observed discrepancy in response to BDNF treatment is an effect of difference in the TrkB expression setting BDNF responsiveness, and of BDNF demands in Sol and TA muscles. [ABSTRACT FROM AUTHOR]

Galectin-3 (Gal-3; formally named MAC-2) is a b-galactoside-binding lectin. Various cell types produce Gal-3 under either normal conditions and/or pathological conditions. Gal-3 can be present in cells' nuclei and cytoplasm, secreted from producing cells, and associated with cells' plasma membranes. This review focuses on how Gal-3 controls phagocytosis and macropinocytosis. Intracellular and extracellular Gal-3 promotes the phagocytosis of phagocytic targets/cargo (e.g., tissue debris and apoptotic cells) in "professional phagocytes" (e.g., microglia and macrophages) and "non-professional phagocytes" (e.g., Schwann cells and astrocytes). Intracellularly, Gal-3 promotes phagocytosis by controlling the "eat me" signaling pathways that phagocytic receptors generate, directing the cytoskeleton to produce the mechanical forces that drive the structural changes on which phagocytosis depends, protrusion and then retraction of filopodia and lamellipodia as they, respectively, engulf and then internalize phagocytic targets. Extracellularly, Gal-3 promotes phagocytosis by functioning as an opsonin, linking phagocytic targets to phagocytic receptors, activating themto generate the "eatme" signaling pathways. Macropinocytosis is a non-selective endocytic mechanism that various cells use to internalize the bulk of extracellular fluid and included materials/cargo (e.g., dissolved nutrients, proteins, and pathogens). Extracellular and intracellular Gal-3 control macropinocytosis in some types of cancer. Phagocytosed and macropinocytosed targets/cargo that reach lysosomes for degradation may rupture lysosomal membranes. Damaged lysosomal membranes undergo either repair or removal by selective autophagy (i.e., lysophagy) that intracellular Gal-3 controls. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain is still a challenge for clinical treatment as a result of the comprehensive pathogenesis. Although emerging evidence demonstrates the pivotal role of glial cells in regulating neuropathic pain, the role of Schwann cells and their underlying mechanisms still need to be uncovered. Pannexin 1 (Panx 1), an important membrane channel for the release of ATP and inflammatory cytokines, as well as its activation in central glial cells, contributes to pain development. Here, we hypothesized that Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain.Methods: A mouse model of chronic constriction injury (CCI) in CD1 adult mice or P0-Cre transgenic mice, and in vitro cultured Schwann cells were used. Intrasciatic injection with Panx 1 blockers or the desired virus was used to knock down the expression of Panx 1. Mechanical and thermal sensitivity was assessed using Von Frey and a hot plate assay. The expression of Panx 1 was measured using qPCR, western blotting, and immunofluorescence. The production of cytokines was monitored through qPCR and enzyme-linked immunosorbent assay (ELISA). Panx1 channel activity was detected by ethidium bromide (EB) uptake.Results: CCI induced persistent neuroinflammatory responses and upregulation of Panx 1 in Schwann cells. Intrasciatic injection of Panx 1 blockers, carbenoxolone (CBX), probenecid, and Panx 1 mimetic peptide (10Panx) effectively reduced mechanical and heat hyperalgesia. Probenecid treatment of CCI-induced mice significantly reduced Panx 1 expression in Schwann cells, but not in dorsal root ganglion (DRG). In addition, Panx 1 knockdown in Schwann cells with Panx 1 shRNA-AAV in P0-Cre mice significantly reduced CCI-induced neuropathic pain. To determine whether Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain, we evaluated its effect in LPS-treated Schwann cells. We found that inhibition of Panx 1 via CBX and Panx 1-siRNA effectively attenuated the production of selective cytokines, as well as its mechanism of action being dependent on both Panx 1 channel activity and its expression.Conclusion: In this study, we found that CCI-related neuroinflammation correlates with Panx 1 activation in Schwann cells, indicating that inhibition of Panx 1 channels in Schwann cells reduces neuropathic pain through the suppression of neuroinflammatory responses. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) is a type of sensory nerve damage that can occur in patients with diabetes. Although the understanding of pathophysiology is incomplete, DN is often associated with structural and functional alterations of the affected neurons. Among all possible causes of nerve damage, Schwann cells (SCs) are thought to play a key role in repairing peripheral nerve injury, suggesting that functional deficits occurring in SCs may potentially exhibit their pathogenic roles in DN. Therefore, elucidating the mechanisms that underlie this pathology can be used to develop novel therapeutic targets. In this regard, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently attracted great attention in ameliorating SCs' dysfunction. However, the detailed mechanisms remain uncertain. In the present study, we investigated how GLP-1 RA Liraglutide protects against RSC96 SCs dysfunction through a diabetic condition mimicked by high glucose and high free fatty acid (FFA). Our results showed that high glucose and high FFAs reduced the viability of RSC96 SCs by up to 51%, whereas Liraglutide reduced oxidative stress by upregulating antioxidant enzymes, and thus protected cells from apoptosis. Liraglutide also inhibited NFκB-mediated inflammation, inducing SCs to switch from pro-inflammatory cytokine production to anti-inflammatory cytokine production. Moreover, Liraglutide upregulated the production of neurotrophic factors and myelination-related proteins, and these protective effects appear to be synergistically linked to insulin signaling. Taken together, our findings demonstrate that Liraglutide ameliorates diabetes-related SC dysfunction through the above-mentioned mechanisms, and suggest that modulating GLP-1 signaling in SCs may be a promising strategy against DN. [ABSTRACT FROM AUTHOR]

Schwannoma, a benign tumor, arise from schwann cells of myelin sheath; occur anywhere in the body but commonly occur on flexor aspect of extremities. Nasal septum being the rarer site. We report a case of nasal septum schwannoma in an 18-year-old female presented with intermittent epistaxis and progressively increasing nasal obstruction for 2-year duration. The differential diagnosis of juvenile angiofibroma, pyogenic granuloma, and pleomorphic adenoma was made and complete surgical excision was done. Histopathological examination revealed ciliated stratified columnar epithelium, underlying tumor area with two distinct patterns, mainly hypercellular and few hypocellular areas. The cells have spindle shaped pointed basophilic nuclei with abundant eosinophilic cytoplasm. Overall feature was suggestive of nasal septum schwannoma. For confirmation, immunohistochemical staining with S-100 was done and tumor was found positive. Herein, we report the clinicopathological features of nasal septum schwannoma in an 18-year-old female. [ABSTRACT FROM AUTHOR]

Objectives: Due to the complex and unclear pathogenesis of neuropathic pain, there is a lack of effective therapeutic strategy. miR-363-5p was considered of great potential in mediating the development of neuropathic pain, which has not been confirmed with direct evidence. This study evaluated the role of miR-363-5p in neuropathic pain with animal and cell models, aiming to reveal the potential of miR-363-5p in target therapy of neuropathic pain., Methods: Chronic constriction injury (CCI) rat models were established as the neuropathic pain model. The expression of miR-363-5p and its target was evaluated by PCR. The painology behaviors were evaluated to assess the function of miR-363-5p. Schwann cells were induced with LPS mimicking cell injury during neuropathic pain. Inflammation and cell growth were estimated by ELISA and CCK8 assays., Results: Significant downregulation of miR-363-5p and upregulation of SERPING1 were observed in CCI rats. miR-363-5p negatively regulated SERPING1 in CCI rats and LPS-induced Schwann cells. Overexpressing miR-363-5p could improve pain threshold and alleviate inflammation in CCI rats. It also a ttenuated LPS-induced inflammation and reduced proliferation in Schwann cells. The overexpression of SERPING1 could reverse the protective effect of miR-363-5p on CCI rats and LPS-induced Schwann cell injury., Conclusion: miR-363-5p protected from neuropathic pain via alleviating Schwann cell injury by negatively modulating SERPING1.

Peripheral nerve injury (PNI) represents a prevalent condition characterized by the demyelination of affected nerves. The challenge of remyelinating these nerves and achieving satisfactory functional recovery has long been a persistent issue. The specific contributions of growth hormone (GH) in the aftermath of PNI have remained ambiguous. Our investigations have demonstrated that GH not only enhances neurological function scores but also promotes remyelination within a three-week period. Further in vivo studies corroborated that GH facilitates nerve function improvement by mitigating neuronal apoptosis. In vitro, the ideal concentration of GH for exerting effects on Schwann cells (SCs) has been identified as 80 ng/mL. Subsequent research uncovered GH's profound impact on SCs proliferation, cell cycle progression, and migration. Through RNA sequencing and additional experiments, it was discovered that GH treatment elevates the phosphorylation levels of IGF-1R, AKT, and ERK. Moreover, the GH-induced proliferation and migration of SCs were significantly diminished by the inhibition of the IGF-1R pathway, achieved through pre-treatment with Linsitinib. The outcomes of this investigation suggest that GH can significantly enhance the proliferation and migration of SCs, presenting it as a viable option for PNI repair., (© 2024 Wiley Periodicals LLC.)

Oral schwannomas are rare, with only 18 cases of soft palate involvement reported since 1985. We report a case of a 15-year-old male with a soft palate schwannoma who was successfully treated by surgical excision and had no complications over a one-year follow-up. Histologically, schwannomas exhibit Antoni A and B patterns., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Diabetic peripheral neuropathy, characterized by symptoms such as paresthesia, neuropathic pain, and potential lower limb amputation, poses significant clinical management challenges. Recent studies suggest that chronic hyperglycemia-induced Schwann cells (SCs) apoptosis contributes to neurodegeneration and impaired nerve regeneration, but the detailed mechanisms are still unknown. Our study investigated a mixed-sex type 2 diabetes mellitus (T2DM) rat model using leptin knockout (KO) to simulate obesity and diabetes-related conditions. Through extensive assessments, including mechanical allodynia, electrophysiology, and microcirculation analyses, along with myelin degradation studies in KO versus wild-type rats, we focused on apoptosis, autophagy, and SCs dedifferentiation in the sciatic nerve and examined nerve regeneration in KO rats. KO rats exhibited notable reductions in mechanical withdrawal force, prolonged latency, decreased compound muscle action potential (CMAP) amplitude, reduced microcirculation, myelin sheath damage, and increases in apoptosis, autophagy, and SCs dedifferentiation. Moreover, leptin KO was found to impair peripheral nerve regeneration postinjury, as indicated by reduced muscle weight, lower CMAP amplitude, extended latency, and decreased remyelination and SCs density. These findings underscore the effectiveness of the T2DM rat model in clarifying the impact of leptin KO on SCs apoptosis, dedifferentiation, and demyelination, providing valuable insights into new therapeutic avenues for treating T2DM-induced peripheral neuropathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate the efficacy of intrathecal combined administration of autologous bone marrow-derived mesenchymal stem cells (BMSCs) and Schwann cells (SCs) in urinary function improvement in complete spinal cord injury (SCI) patients for the first time., Methods: This study was a randomized phase II clinical trial, including treatment and control arms. Patients with traumatic complete SCI-induced neurogenic bladder were included. The treatment group received a single intrathecal combined injection of autologous BMSCs and SCs. The control group underwent no additional intervention. The outcome measures of the study were urodynamic study parameters, number of incontinence and urinary tract infection episodes, incontinence quality of life questionnaire, functional status, and sensorimotor improvements., Results: Among a total of 32 recruited patients, 13 and 16 were completely followed up in the treatment and control group, respectively. Changes in bladder compliance (P = 0.032), maximum pressure of detrusor during the filling phase (P = 0.013), maximum pressure of detrusor at the maximum urinary flow rate (P = 0.020), maximum urinary flow rate (P = 0.001), and postvoid residual volume (P = 0.001) after 6 months were significantly different between the 2 groups. The number of urinary incontinence episodes (P = 0.022) significantly reduced in the treatment group after 6 months compared with the baseline. The incontinence quality of life total and domain scores significantly improved in the treatment group compared with the control group after 6 months., Conclusions: The combined intrathecal administration of BMSCs and SCs significantly improved the urodynamic study parameters, urinary incontinence rate, and incontinence quality of life in complete SCI-induced neurogenic bladder., (Copyright © 2024. Published by Elsevier Inc.)

To restore function after nerve injury, axons must regenerate from the injury site to the periphery, then reinnervate appropriate end organs when they arrive. Only 10 % of adults who suffer nerve injury will regain normal function, often because axons regenerate to functionally inappropriate targets (Brushart, 2011). The peripheral destination of these axons is largely determined by the pathways they enter at the site of nerve repair. To improve clinical outcomes, it is thus critical to improve the accuracy of axon pathfinding. In rodents, motor axons regenerating in mixed nerve preferentially reinnervate pathways leading to muscle, a process termed preferential motor reinnervation (PMR). Previous experiments have shown that PMR can be enhanced by predegenerating nerve grafts to enhance growth factor production and remove inhibitory factors (Abdullah et al., 2013). The current experiments explore the relative contributions of motor pathways, sensory pathways, and the repair environment to this enhancement. Sensory and/or motor pathways within rat femoral nerve grafts were predegenerated for 3 weeks to optimize growth factor production (Brushart et al., 2013) or for 12 weeks to deplete it. Optimizing the environment within previously motor Schwann cell tubes promoted PMR, regardless of whether adjacent sensory pathways were optimized or chronically denervated. However, this positive effect was abolished when sensory pathways were undergoing acute Wallerian degeneration immediately after nerve repair. The repair environment thus precluded motor axon pathfinding in spite of an optimized distal motor pathway. When sensory pathways were optimized and motor pathways were chronically denervated, not only was PMR abolished, but motoneurons failed to respond to the greater volume of growth factors in the sensory nerve. Small sensory neurons, however, selectively reinnervated cutaneous nerve under these conditions. These experiments thus strengthen the concept that, in adult rats, sensory and motor pathways have unique identities capable of influencing both sensory and motor axon regeneration. Furthermore, they demonstrate that, in the rat, delaying nerve repair for 3 weeks to enhance growth factor production and clear the products of acute Wallerian degeneration can enhance regeneration specificity without the need for exogenous treatments., Competing Interests: Declaration of competing interest I certify that none of the authors of this paper have any conflict of interest of an academic or financial nature., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Schwann cells are glial cells in the peripheral nervous system (PNS); they wrap neuronal axons with their differentiated plasma membranes called myelin sheaths. Although the physiological functions, such as generating saltatory conduction, have been well studied in the PNS, the molecular mechanisms by which Schwann cells undergo their differentiation program without apparent morphological changes before dynamic myelin sheath formation remain unclear. Here, for the first time, we report that Arf6, a small GTP/GDP-binding protein controlling morphological differentiation, and the guanine-nucleotide exchange factors cytohesin proteins are involved in the regulation of Schwann cell differentiation marker expression in primary Schwann cells. Specific inhibition of Arf6 and cytohesins by NAV-2729 and SecinH3, respectively, decreased expression of marker proteins 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and glial fibrillary acidic protein (GFAP). Similar results using promoter assays were observed using the IMS32 Schwann cell line. Furthermore, using an affinity-precipitation technique, we identified Bcl2-like 12 (Bcl2l12) as a novel GTP-bound Arf6-interacting protein. Knockdown of Bcl2l12 using a specific artificial miRNA decreased expression of marker proteins. The knockdown also led to decreased filamentous actin extents. These results suggest that Arf6 and Bcl2l12 can trigger Schwann cell differentiation, providing evidence for a molecular relay that underlies how Schwann cells differentiate., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Rapid nerve conduction in the peripheral nervous system (PNS) is facilitated by the multilamellar myelin sheath encasing many axons of peripheral nerves. Charcot-Marie-Tooth type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsy (HNPP) are common demyelinating inherited peripheral neuropathies and are caused by mutations in the peripheral myelin protein 22 (PMP22) gene. Duplication of PMP22 leads to its overexpression and causes CMT1A, while its deletion results in PMP22 under expression and causes HNPP. Here, we investigated novel targets for modulating the protein level of PMP22 in HNPP. We found that genetic attenuation of the transcriptional coactivator Yap in Schwann cells reduces p-TAZ levels, increased TAZ activity, and increases PMP22 in peripheral nerves. Based on these findings, we ablated Yap alleles in Schwann cells of the Pmp22-haploinsufficient mouse model of HNPP and identified fewer tomacula on morphological assessment and improved nerve conduction in peripheral nerves. These findings suggest YAP modulation may be a new avenue for treatment of HNPP., (© 2024 Wiley Periodicals LLC.)

The Schwann cell (SC) is essential in peripheral nerve regeneration by reprogramming into a stem-like "repair Schwann cell" (rSC) phenotype; however, maintaining the rSC stemness remains an unmet challenge. Chirality is a fundamental factor controlling cell fate, and its potential role in regulation of SC reprogramming has long been ignored and remains poorly understood. Herein, inspired by natural chiral components in the SC microenvironment, chiral hydrogel nerve conduits are prepared by supramolecular assembly of l/d-phenylalanine derivatives (l/d-Phe) in polymeric chitosan-gelatin conduits. Right-handed l-Phe fibers within hydrogel conduits maintain the stemness of rSC through enhanced stereoselective interaction between collagen IV and l-Phe fibers triggered by collagen IV-Integrin α1β1, MAPK, and YAP/TAZ signaling pathways and finally activate the key regulator of SC reprogramming, the c-Jun pathway. In the rat model of a sciatic nerve defect, the l-Phe hydrogel nerve conduit significantly enhances nerve regeneration, exhibiting markedly improved histological, electrophysiological, and functional outcomes. The findings reveal the chirality-dependent regulation of SC reprogramming in a pioneering way, offering potential strategies for nerve regeneration therapies.

Abstract Background Lysophosphatidic acid (LPA) is a pleiotropic lipid messenger that addresses at least six specific G-protein coupled receptors. Accumulating evidence indicates a significant involvement of LPA in immune cell regulation as well as Schwann cell physiology, with potential relevance for the pathophysiology of peripheral neuroinflammation. However, the role of LPA signaling in inflammatory neuropathies has remained completely undefined. Given the broad expression of LPA receptors on both Schwann cells and cells of the innate and adaptive immune system, we hypothesized that inhibition of LPA signaling may ameliorate the course of disease in experimental autoimmune neuritis (EAN). Methods We induced active EAN by inoculation of myelin protein 2 peptide (P255–78) in female Lewis rats. Animals received the orally available LPA receptor antagonist AM095, specifically targeting the LPA1 receptor subtype. AM095 was administered daily via oral gavage in a therapeutic regimen from 10 until 28 days post-immunization (dpi). Analyses were based on clinical testing, hemogram profiles, immunohistochemistry and morphometric assessment of myelination. Results Lewis rats treated with AM095 displayed a significant improvement in clinical scores, most notably during the remission phase. Cellular infiltration of sciatic nerve was only discretely affected by AM095. Hemogram profiles indicated no impact on circulating leukocytes. However, sciatic nerve immunohistochemistry revealed a reduction in the number of Schwann cells expressing the dedifferentiation marker Sox2 paralleled by a corresponding increase in differentiating Sox10-positive Schwann cells. In line with this, morphometric analysis of sciatic nerve semi-thin sections identified a significant increase in large-caliber myelinated axons at 28 dpi. Myelin thickness was unaffected by AM095. Conclusion Thus, LPA1 signaling may present a novel therapeutic target for the treatment of inflammatory neuropathies, potentially affecting regenerative responses in the peripheral nerve by modulating Schwann cell differentiation.

Traumatic peripheral nerve injury occurs frequently and is a major clinical and public health problem that can lead to functional impairment and permanent disability. Despite the availability of modern diagnostic procedures and advanced microsurgical techniques, active recovery after peripheral nerve repair is often unsatisfactory. Peripheral nerve regeneration involves several critical events, including the recreation of the microenvironment and remyelination. Results from previous studies suggest that the peripheral nervous system (PNS) has a greater capacity for repair than the central nervous system. Thus, it will be important to understand myelin and myelination specifically in the PNS. This review provides an update on myelin biology and myelination in the PNS and discusses the mechanisms that promote myelin clearance after injury. The roles of Schwann cells and macrophages are considered at length, together with the possibility of exogenous intervention.

This paper examines the epistemological history of physiological tissue regeneration theories from Antiquity to the present time focusing on early clinical observations, microscopic investigations of the 19th C. and molecular aspects of the regeneration of peripheral nerves. We aim to show underlying theoretical implications at stake over centuries, with an extreme diversity of local contexts, while slowly emerging ideas were progressively built in the framework of cell theory and that of molecular biology. The overall epistemological lesson is that this long history is far from finished and requires novel experiments and perspectives, as well as the careful inspection of its rich past, as a true scientific tradition, in order to better understand what is nervous regeneration and how we can use it in medicine.

Galectin-3 (Gal-3; formally named MAC-2) is a β-galactoside-binding lectin. Various cell types produce Gal-3 under either normal conditions and/or pathological conditions. Gal-3 can be present in cells' nuclei and cytoplasm, secreted from producing cells, and associated with cells' plasma membranes. This review focuses on how Gal-3 controls phagocytosis and macropinocytosis. Intracellular and extracellular Gal-3 promotes the phagocytosis of phagocytic targets/cargo (e.g., tissue debris and apoptotic cells) in “professional phagocytes” (e.g., microglia and macrophages) and “non-professional phagocytes” (e.g., Schwann cells and astrocytes). Intracellularly, Gal-3 promotes phagocytosis by controlling the “eat me” signaling pathways that phagocytic receptors generate, directing the cytoskeleton to produce the mechanical forces that drive the structural changes on which phagocytosis depends, protrusion and then retraction of filopodia and lamellipodia as they, respectively, engulf and then internalize phagocytic targets. Extracellularly, Gal-3 promotes phagocytosis by functioning as an opsonin, linking phagocytic targets to phagocytic receptors, activating them to generate the “eat me” signaling pathways. Macropinocytosis is a non-selective endocytic mechanism that various cells use to internalize the bulk of extracellular fluid and included materials/cargo (e.g., dissolved nutrients, proteins, and pathogens). Extracellular and intracellular Gal-3 control macropinocytosis in some types of cancer. Phagocytosed and macropinocytosed targets/cargo that reach lysosomes for degradation may rupture lysosomal membranes. Damaged lysosomal membranes undergo either repair or removal by selective autophagy (i.e., lysophagy) that intracellular Gal-3 controls.

Previous in vitro and in vivo studies have indicated that tissue engineering scaffolds, including Schwann cells, may improve axonal regeneration, particularly in combination with Methylprednisolone as an influential neuroprotective factor. The primary aim of this study was to design composite electrospun scaffolds based on polylactic acid (PLA)/hyaluronic acid (HA) containing various percentages (0.05–2% (w/v)) of Methylprednisolone (MP) with suitable mechanical and chemical properties for soft tissue especially to promote nerve growth. For the first time, MP was implicated in a PLA/HA nanofibrous and its effect on fiber's properties was scrutinized as a candidate for nerve tissue engineering. In addition, morphology, chemical bonding, wettability, and degradation of the scaffolds were examined to evaluate their performance. The results showed the PLA/HA scaffolds had suitable morphological, physicochemical, and mechanical properties for nerve regeneration. Also, various percentages of MP were evaluated through physiochemical assay, drug release profile, and biological assays to find an optimum level of drug. These scaffolds may improve the growth and viability of Schwann cells. Results showed that composite scaffolds containing 0.5 w/v MP had lower cytotoxicity and higher biocompatibility. Graphical Abstract [ABSTRACT FROM AUTHOR]

Functional recovery after peripheral nerve injuries is critically dependent on axonal regeneration. Several autonomous and non-cell autonomous processes regulate axonal regeneration, including the activation of a growth-associated transcriptional program in neurons and the reprogramming of dierentiated Schwann cells (dSCs) into repair SCs (rSCs), triggering the secretion of neurotrophic factors and the activation of an inflammatory response. Repair Schwann cells also release pro-regenerative extracellular vesicles (EVs), but is still unknown whether EV secretion is regulated non-cell autonomously by the regenerating neuron. Interestingly, it has been described that nerve activity enhances axonal regeneration by increasing the secretion of neurotrophic factors by rSC, but whether this activity modulates proregenerative EV secretion by rSC has not yet been explored. Here, we demonstrate that neuronal activity enhances the release of rSC-derived EVs and their transfer to neurons. This eect is mediated by activation of P2Y receptors in SCs after activity-dependent ATP release from sensory neurons. Importantly, activation of P2Y in rSCs also increases the amount of miRNA-21 present in rSC-EVs. Taken together, our results demonstrate that neuron to glia communication by ATP-P2Y signaling regulates the content of SC-derived EVs and their transfer to axons, modulating axonal elongation in a non-cell autonomous man. [ABSTRACT FROM AUTHOR]

Our laboratory reported the derivation of neural crest stem cell (NCSC)-like cells from the interfollicular epidermis of the neonatal and adult epidermis. These keratinocyte (KC)-derived Neural Crest (NC)-like cells (KC-NC) could differentiate into functional neurons, Schwann cells (SC), melanocytes, and smooth muscle cells in vitro. Most notably, KC-NC migrated along stereotypical pathways and gave rise to multiple NC derivatives upon transplantation into chicken embryos, corroborating their NC phenotype. Here, we present an innovative design concept for developing anisotropically aligned scaffolds with chemically immobilized biological cues to promote differentiation of the KC-NC towards the SC. Specifically, we designed electrospun nanofibers and examined the effect of bioactive cues in guiding KC-NC differentiation into SC. KC-NC attached to nanofibers and adopted a spindle-like morphology, similar to the native extracellular matrix (ECM) microarchitecture of the peripheral nerves. Immobilization of biological cues, especially Neuregulin1 (NRG1) promoted the differentiation of KC-NC into the SC lineage. This study suggests that poly-ε-caprolactone (PCL) nanofibers decorated with topographical and cell-instructive cues may be a potential platform for enhancing KC-NC differentiation toward SC. [ABSTRACT FROM AUTHOR]

Schwann cells (SCs) migrate along peripheral axons and divide intensively to generate the right number of cells prior to axonal ensheathment; however, little is known regarding the temporal and molecular control of their division and its impact on myelination. We report that Sil, a spindle pole protein associated with autosomal recessive primary microcephaly, is required for temporal mitotic exit of SCs. In sil-deficient Cassiopeia (csp-1-) mutants, SCs fail to radially sort and myelinate peripheral axons. Elevation of cAMP, but not Rac1 activity, in csp-1- restores myelin ensheathment. Most importantly, we show a significant decrease in laminin expression within csp-1- posterior lateral line nerve and that forcing Laminin 2 expression in csp-1- fully restores the ability of SCs to myelinate. Thus, we demonstrate an essential role for timely SC division in mediating laminin expression to orchestrate radial sorting and peripheral myelination in vivo. [ABSTRACT FROM AUTHOR]