GFP-labeled Schwann cell-like cells derived from hair follicle epidermal neural crest stem cells promote the acellular nerve allografts to repair facial nerve defects in rats.

BACKGROUND: Acellular nerve allografts (ANAs) have been successfully applied to bridge facial nerve defects, and transplantation of stem cells may enhance the regenerative results. Up to now, application of hair follicle epidermal neural crest stem cell-derived Schwann cell-like cells (EPI-NCSC-SCLCs) combined with ANAs for bridging facial nerve defects has not been reported. METHODS: The effect of ANAs laden with green fluorescent protein (GFP)-labeled EPI-NCSC-SCLCs (ANA + cells) on bridging rat facial nerve trunk defects (5-mm-long) was detected by functional and morphological examination, as compared with autografts and ANAs, respectively. RESULTS: (1) EPI-NCSC-SCLCs had good compatibility with ANAs in vitro. (2) In the ANA + cells group, the GFP signals were observed by in vivo imaging system for small animals within 8 weeks, and GFP-labeled EPI-NCSC-SCLCs were detected in the tissue slices at 16 weeks postoperatively. (3) The facial symmetry at rest after surgery in the ANA + cells group was better than that in the ANA group (p < 0.05), and similar to that in the autograft group (p > 0.05). The initial recovery time of vibrissal and eyelid movement in the ANA group was 2 weeks later than that in the other two groups. (4) The myelinated fibers, myelin sheath thickness and diameter of the axons of the buccal branches in the ANA group were significantly worse than those in the other two groups (P < 0.05), and the results in the ANA + cells group were similar to those in the autograft group (p > 0.05). CONCLUSIONS: EPI-NCSC-SCLCs could promote functional and morphological recovery of rat facial nerve defects, and GFP labeling could track the transplanted EPI-NCSC-SCLCs in vivo for a certain period of time. These may provide a novel choice for clinical treatment of peripheral nerve defects.

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

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

Chitosan Nerve Grafts Incorporated with SKP-SC-EVs Induce Peripheral Nerve Regeneration.

BACKGROUND: Repair of long-distance peripheral nerve defects remains an important clinical problem. Nerve grafts incorporated with extracellular vesicles (EVs) from various cell types have been developed to bridge peripheral nerve defects. In our previous research, EVs obtained from skin-derived precursor Schwann cells (SKP-SC-EVs) were demonstrated to promote neurite outgrowth in cultured cells and facilitate nerve regeneration in animal studies. METHODS: To further assess the functions of SKP-SC-EVs in nerve repair, we incorporated SKP-SC-EVs and Matrigel into chitosan nerve conduits (EV-NG) for repairing a 15-mm long-distance sciatic nerve defect in a rat model. Behavioral analysis, electrophysiological recording, histological investigation, molecular analysis, and morphometric assessment were carried out. RESULTS: The results revealed EV-NG significantly improved motor and sensory function recovery compared with nerve conduits (NG) without EVs incorporation. The outgrowth and myelination of regenerated axons were improved, while the atrophy of target muscles induced by denervation was alleviated after EVs addition. CONCLUSION: Our data indicated SKP-SC-EVs incorporation into nerve grafts represents a promising method for extended peripheral nerve damage repair.

Enhancing Functional Recovery after Segmental Nerve Defect Using Nerve Allograft Treated with Plasma-Derived Exosome.

BACKGROUND: Nerve injuries can result in detrimental functional outcomes. Currently, autologous nerve graft offers the best outcome for segmental peripheral nerve injury. Allografts are alternatives, but do not have comparable results. This study evaluated whether plasma-derived exosome can improve nerve regeneration and functional recovery when combined with decellularized nerve allografts. METHODS: The effect of exosomes on Schwann cell proliferation and migration were evaluated. A rat model of sciatic nerve repair was used to evaluate the effect on nerve regeneration and functional recovery. A fibrin sealant was used as the scaffold for exosome. Eighty-four Lewis rats were divided into autograft, allograft, and allograft with exosome groups. Gene expression of nerve regeneration factors was analyzed on postoperative day 7. At 12 and 16 weeks, rats were subjected to maximum isometric tetanic force and compound muscle action potential. Nerve specimens were then analyzed by means of histology and immunohistochemistry. RESULTS: Exosomes were readily taken up by Schwann cells that resulted in improved Schwann cell viability and migration. The treated allograft group had functional recovery (compound muscle action potential, isometric tetanic force) comparable to that of the autograft group. Similar results were observed in gene expression analysis of nerve regenerating factors. Histologic analysis showed no statistically significant differences between treated allograft and autograft groups in terms of axonal density, fascicular area, and myelin sheath thickness. CONCLUSIONS: Plasma-derived exosome treatment of decellularized nerve allograft may provide comparable clinical outcomes to that of an autograft. This can be a promising strategy in the future as an alternative for segmental peripheral nerve repair. CLINICAL RELEVANCE STATEMENT: Off-the-shelf exosomes may improve recovery in nerve allografts.

Large-gap peripheral nerve repair using xenogeneic transplants in rhesus macaques.

Surgical intervention is required to successfully treat severe, large-gap (≥4 cm) peripheral nerve injuries. However, all existing treatments have shortcomings and an alternative to the use of autologous nerves is needed. Human and porcine nerves are physiologically similar, with comparable dimensions and architecture, presence and distribution of Schwann cells, and conserved features of the extracellular matrix (ECM). We report the repair of fully transected radial nerves in 10 Rhesus Macaques using viable, whole sciatic nerve from genetically engineered (GalT-KO), designated pathogen free (DPF) porcine donors. This resulted in the regeneration of the transected nerve, and importantly, recovery of wrist extension function, distal muscle reinnervation, and recovery of nerve conduction velocities and compound muscle action potentials similar to autologous controls. We also demonstrate the absence of immune rejection, systemic porcine cell migration, and detectable residual porcine material. Our preliminary findings support the safety and efficacy of viable porcine nerve transplants, suggest the interchangeable therapeutic use of cross-species cells, and highlight the broader clinical potential of xenotransplantation.

Acellular nerve grafts with bone marrow mesenchymal stem cells/Schwann cells for sciatic nerve regeneration in rats: a meta-analysis.

INTRODUCTION: The aim of this meta-analysis was to evaluate the effects of acellular nerve grafts (ANGs) with bone marrow mesenchymal stem cells (BMSCs) or Schwann cells (SCs) on the treatment of sciatic nerve defect in rats. EVIDENCE ACQUISITION: Electronic databases were accessed to identify eligible targets. ANGs data were extracted for meta-analysis using Review Manager 5.3. EVIDENCE SYNTHESIS: The rats subjected to ANGs+BMSCs or ANGs+SCs are characterized by different sciatic nerve function index, nerve conduction, latency, amplitude, myelin sheath thickness, myelinated nerve fibers and gastrocnemius wet weight. accompanied with evidently superior recovery of limb function. These differences are of statistical significance (P<0.05) when compared to that of control group with ANGs only. CONCLUSIONS: ANGs with BMSCs or SCs can promote nerve regeneration and functional recovery in peripheral nerve defects.

Sequential oxygen supply system promotes peripheral nerve regeneration by enhancing Schwann cells survival and angiogenesis.

Local hypoxia in cellular grafts remains a challenge during the repair of peripheral nerve injury. Oxygen carriers (perfluorotributylamine, PFTBA) have been shown to provide oxygen to Schwann cells (SCs) for a short period. However, the limited oxygen supply from oxygen-carrying materials hinders the ability of such systems to counteract hypoxia over an extended period and limits their therapeutic potential. In this study, PFTBA/VEGF core-shell fibers were fabricated through coaxial electrospinning to construct an oxygen supply system that can sequentially provide oxygen, first via the oxygen carrier and subsequently by promoting angiogenesis via VEGF. Then, the oxygen release and proangiogenic effects of the PFTBA/VEGF core-shell fibers were examined in vitro. Furthermore, sequential oxygen supply conduits prepared using the fibers and filled with SCs were used to bridge 15-mm-long sciatic nerve defects in rats. The PFTBA-VEGF system was confirmed to protect SCs from hypoxia and promote angiogenesis in vitro. Subsequent in vivo studies showed that after the oxygen carried by PFTBA was exhausted, the VEGF could induce neovascularization, and the nascent blood vessels acted as sequential oxygen suppliers for SCs during nerve regeneration. In addition, rats transplanted with the sequential oxygen supply system showed significant morphological and functional improvements in axonal regeneration, the sciatic function index, and the muscle wet weight ratio. The final functional outcomes were similar after treatment with the sequential oxygen supply conduits and autografts. Western blots revealed that the VEGF in the system could upregulate p-AMPK, contributing to axon regeneration after sciatic nerve injury. The sequential oxygen supply system offers essential insights into the oxygen regulation of biomaterials and highlights the potential of oxygen supply strategies as therapeutic approaches for repairing defects in peripheral nerves and other aerobic tissues.

Brachial plexus bridging with specific extracellular matrix-modified chitosan/silk scaffold: a new expand of tissue engineered nerve graft.

Objective.Brachial plexus injuries (BPIs) result in serious dysfunction, especially brachial plexus defects which are currently treated using autologous nerve graft (autograft) transplantation. With the development of tissue engineering, tissue engineered nerve grafts (TENGs) have emerged as promising alternatives to autografts but have not yet been widely applied to the treatment of BPIs. Herein, we developed a TENG modified with extracellular matrix generated by skin-derived precursor Schwann cells (SKP-SCs) and expand its application in upper brachial plexus defects in rats.Approach.SKP-SCs were co-cultured with chitosan neural conduits or silk fibres and subjected to decellularization treatment. Ten bundles of silk fibres (five fibres per bundle) were placed into a conduit to obtain the TENG, which was used to bridge an 8 mm gap in the upper brachial plexus. The efficacy of this treatment was examined for TENG-, autograft- and scaffold-treated groups at several times after surgery using immunochemical staining, behavioural tests, electrophysiological measurements, and electron microscopy.Main results.Histological analysis conducted two weeks after surgery showed that compared to scaffold bridging, TENG treatment enhanced the growth of regenerating axons. Behavioural tests conducted four weeks after surgery showed that TENG-treated rats performed similarly to autograft-treated ones, with a significant improvement observed in both cases compared with the scaffold treatment group. Electrophysiological and retrograde tracing characterizations revealed that the target muscles were reinnervated in both TENG and autograft groups, while transmission electron microscopy and immunohistochemical staining showed the occurrence of the superior myelination of regenerated axons in these groups.Significance.Treatment with the developed TENG allows the effective bridging of proximal nerve defects in the upper extremities, and the obtained results provide a theoretical basis for clinical transformation to expand the application scope of TENGs.

In vitro modulation of Schwann cell behavior by VEGF and PDGF in an inflammatory environment.

Peripheral glial cell transplantation with Schwann cells (SCs) is a promising approach for treating spinal cord injury (SCI). However, improvements are needed and one avenue to enhance regenerative functional outcomes is to combine growth factors with cell transplantation. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are neuroprotective, and a combination of these factors has improved outcomes in rat SCI models. Thus, transplantation of SCs combined with VEGF and PDGF may further improve regenerative outcomes. First, however, we must understand how the two factors modulate SCs. In this in vitro study, we show that an inflammatory environment decreased the rate of SC-mediated phagocytosis of myelin debris but the addition of VEGF and PDGF (alone and combined) improved phagocytosis. Cytokine expression by SCs in the inflammatory environment revealed that addition of PDGF led to significantly lower level of pro-inflammatory cytokine, TNF-α, but IL-6 and anti-inflammatory cytokines (TGF-ß and IL-10), remained unaltered. Further, PDGF was able to decrease the expression of myelination associated gene Oct6 in the presence of inflammatory environment. Overall, these results suggest that the use of VEGF and/or PDGF combined with SC transplantation may be beneficial in SCI therapy.

Augmenting Peripheral Nerve Regeneration with Adipose-Derived Stem Cells.

Peripheral nerve injuries (PNIs) are common and debilitating, cause significant health care costs for society, and rely predominately on autografts, which necessitate grafting a nerve section non-locally to repair the nerve injury. One possible approach to improving treatment is bolstering endogenous regenerative mechanisms or bioengineering new nervous tissue in the peripheral nervous system. In this review, we discuss critical-sized nerve gaps and nerve regeneration in rats, and summarize the roles of adipose-derived stem cells (ADSCs) in the treatment of PNIs. Several regenerative treatment modalities for PNI are described: ADSCs differentiating into Schwann cells (SCs), ADSCs secreting growth factors to promote peripheral nerve growth, ADSCs promoting myelination growth, and ADSCs treatments with scaffolds. ADSCs' roles in regenerative treatment and features are compared to mesenchymal stem cells, and the administration routes, cell dosages, and cell fates are discussed. ADSCs secrete neurotrophic factors and exosomes and can differentiate into Schwann cell-like cells (SCLCs) that share features with naturally occurring SCs, including the ability to promote nerve regeneration in the PNS. Future clinical applications are also discussed.

Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury.

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (n = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.

BMSC-derived extracellular matrix better optimizes the microenvironment to support nerve regeneration.

A favorable microenvironment plays an important role in nerve regeneration. Extracellular matrix (ECM) derived from cultured cells or natural tissues can facilitate nerve regeneration in the presence of various microenvironmental cues, including biochemical, spatial, and biomechanical factors. This study, through proteomics and three-dimensional image analysis, determines that the components and spatial organization of the ECM secreted by bone marrow mesenchymal cells (BMSCs) are more similar to acellular nerves than those of the ECMs derived from Schwann cells (SCs), skin-derived precursor Schwann cells (SKP-SCs), or fibroblasts (FBs). ECM-modified nerve grafts (ECM-NGs) are engineered by co-cultivating BMSCs, SCs, FBs, SKP-SCs with well-designed nerve grafts used to bridge nerve defects. BMSC-ECM-NGs exhibit the most promising nerve repair properties based on the histology, neurophysiology, and behavioral analyses. The regeneration microenvironment formed by the ECM-NGs is also characterized by proteomics, and the advantages of BMSC-ECM-NGs are evidenced by the enhanced expression of factors related to neural regeneration and reduced immune response. Together, these findings indicate that BMSC-derived ECMs create a more superior microenvironment for nerve regeneration than that by the other ECMs and may, therefore, represent a potential alternative for the clinical repair of peripheral nerve defects.

Scalable culture techniques to generate large numbers of purified human Schwann cells for clinical trials in human spinal cord and peripheral nerve injuries.

OBJECTIVE: Schwann cells (SCs) have been shown to play an essential role in axon regeneration in both peripheral nerve injuries (PNIs) and spinal cord injuries (SCIs). The transplantation of SCs as an adjunctive therapy is currently under investigation in human clinical trials due to their regenerative capacity. Therefore, a reliable method for procuring large quantities of SCs from peripheral nerves is necessary. This paper presents a well-developed, validated, and optimized manufacturing protocol for clinical-grade SCs that are compliant with Current Good Manufacturing Practices (CGMPs). METHODS: The authors evaluated the SC culture manufacturing data from 18 clinical trial participants who were recruited for autologous SC transplantation due to subacute SCI (n = 7), chronic SCI (n = 8), or PNIs (n = 3). To initiate autologous SC cultures, a mean nerve length of 11.8 ± 3.7 cm was harvested either from the sural nerve alone (n = 17) or with the sciatic nerve (n = 1). The nerves were digested with enzymes and SCs were isolated and further expanded in multiple passages to meet the dose requirements for transplantation. RESULTS: An average yield of 87.2 ± 89.2 million cells at P2 and 150.9 ± 129.9 million cells at P3 with high viability and purity was produced. Cell counts and rates of expansion increased with each subsequent passage from P0 to P3, with the largest rate of expansion between P2 and P3. Larger harvest nerve lengths correlated significantly with greater yields at P0 and P1 (p < 0.05). In addition, a viability and purity above 90% was sustained throughout all passages in nearly all cell products. CONCLUSIONS: This study presents reliable CGMP-compliant manufacturing methods for autologous SC products that are suitable for regenerative treatment of patients with SCI, PNI, or other conditions.

The Efficacy of Schwann-Like Differentiated Muscle-Derived Stem Cells in Treating Rodent Upper Extremity Peripheral Nerve Injury.

BACKGROUND: There is a pressing need to identify alternative mesenchymal stem cell sources for Schwann cell cellular replacement therapy, to improve peripheral nerve regeneration. This study assessed the efficacy of Schwann cell-like cells (induced muscle-derived stem cells) differentiated from muscle-derived stem cells (MDSCs) in augmenting nerve regeneration and improving muscle function after nerve trauma. METHODS: The Schwann cell-like nature of induced MDSCs was characterized in vitro using immunofluorescence, flow cytometry, microarray, and reverse-transcription polymerase chain reaction. In vivo, four groups (n = 5 per group) of rats with median nerve injuries were examined: group 1 animals were treated with intraneural phosphate-buffered saline after cold and crush axonotmesis (negative control); group 2 animals were no-injury controls; group 3 animals were treated with intraneural green fluorescent protein-positive MDSCs; and group 4 animals were treated with green fluorescent protein-positive induced MDSCs. All animals underwent weekly upper extremity functional testing. Rats were euthanized 5 weeks after treatment. The median nerve and extrinsic finger flexors were harvested for nerve histomorphometry, myelination, muscle weight, and atrophy analyses. RESULTS: In vitro, induced MDSCs recapitulated native Schwann cell gene expression patterns and up-regulated pathways involved in neuronal growth/signaling. In vivo, green fluorescent protein-positive induced MDSCs remained stably transformed 5 weeks after injection. Induced MDSC therapy decreased muscle atrophy after median nerve injury (p = 0.0143). Induced MDSC- and MDSC-treated animals demonstrated greater functional muscle recovery when compared to untreated controls (hand grip after induced MDSC treatment: group 1, 0.91 N; group 4, 3.38 N); p < 0.0001) at 5 weeks after treatment. This may demonstrate the potential beneficial effects of MDSC therapy, regardless of differentiation stage. CONCLUSION: Both MDSCs and induced MDSCs decrease denervation muscle atrophy and improve subsequent functional outcomes after upper extremity nerve trauma in rodents.

SKP-SCs transplantation alleviates 6-OHDA-induced dopaminergic neuronal injury by modulating autophagy.

Parkinson's disease is a common neurodegenerative disease. Cell transplantation is a promising therapeutic option for improving the survival and function of dopaminergic neurons, but the mechanisms underlying the interaction between the transplanted cells and the recipient neurons remain to be studied. In this study, we investigated the effects of skin precursor cell-derived Schwann cells (SKP-SCs) directly cocultured with 6-OHDA-injured dopaminergic neurons in vitro and of SKP-SCs transplanted into the brains of 6-OHDA-induced PD mice in vivo. In vitro and in vivo studies revealed that SKP-SCs could reduce the damage to dopaminergic neurons by enhancing self-autophagy and modulating neuronal autophagy. Thus, the present study provides the first evidence that cell transplantation mitigates 6-OHDA-induced damage to dopaminergic neurons by enhancing self-autophagy, suggesting that earlier transplantation of Schwann cells might help alleviate the loss of dopaminergic neurons.

Functional Outcomes of Nerve Allografts Seeded with Undifferentiated and Differentiated Mesenchymal Stem Cells in a Rat Sciatic Nerve Defect Model.

BACKGROUND: Mesenchymal stem cells have the potential to produce neurotrophic growth factors and establish a supportive microenvironment for neural regeneration. The purpose of this study was to determine the effect of undifferentiated and differentiated mesenchymal stem cells dynamically seeded onto decellularized nerve allografts on functional outcomes when used in peripheral nerve repair. METHODS: In 80 Lewis rats, a 10-mm sciatic nerve defect was reconstructed with (1) autograft, (2) decellularized allograft, (3) decellularized allograft seeded with undifferentiated mesenchymal stem cells, or (4) decellularized allograft seeded with mesenchymal stem cells differentiated into Schwann cell-like cells. Nerve regeneration was evaluated over time by cross-sectional tibial muscle ultrasound measurements, and at 12 and 16 weeks by isometric tetanic force measurements, compound muscle action potentials, muscle mass, histology, and immunofluorescence analyses. RESULTS: At 12 weeks, undifferentiated mesenchymal stem cells significantly improved isometric tetanic force measurement and compound muscle action potential outcomes compared to decellularized allograft alone, whereas differentiated mesenchymal stem cells significantly improved compound muscle action potential outcomes. The autografts outperformed both stem cell groups histologically at 12 weeks. At 16 weeks, functional outcomes normalized between groups. At both time points, the effect of undifferentiated versus differentiated mesenchymal stem cells was not significantly different. CONCLUSIONS: Undifferentiated and differentiated mesenchymal stem cells significantly improved functional outcomes of decellularized allografts at 12 weeks and were similar to autograft results in the majority of measurements. At 16 weeks, outcomes normalized as expected. Although differences between both cell types were not statistically significant, undifferentiated mesenchymal stem cells improved functional outcomes of decellularized nerve allografts to a greater extent and had practical benefits for clinical translation by limiting preparation time and costs.

Electroacupuncture facilitates the integration of a grafted TrkC-modified mesenchymal stem cell-derived neural network into transected spinal cord in rats via increasing neurotrophin-3.

AIMS: This study was aimed to investigate whether electroacupuncture (EA) would increase the secretion of neurotrophin-3 (NT-3) from injured spinal cord tissue, and, if so, whether the increased NT-3 would promote the survival, differentiation, and migration of grafted tyrosine kinase C (TrkC)-modified mesenchymal stem cell (MSC)-derived neural network cells. We next sought to determine if the latter would integrate with the host spinal cord neural circuit to improve the neurological function of injured spinal cord. METHODS: After NT-3-modified Schwann cells (SCs) and TrkC-modified MSCs were co-cultured in a gelatin sponge scaffold for 14 days, the MSCs differentiated into neuron-like cells that formed a MSC-derived neural network (MN) implant. On this basis, we combined the MN implantation with EA in a rat model of spinal cord injury (SCI) and performed immunohistochemical staining, neural tracing, electrophysiology, and behavioral testing after 8 weeks. RESULTS: Electroacupuncture application enhanced the production of endogenous NT-3 in damaged spinal cord tissues. The increase in local NT-3 production promoted the survival, migration, and maintenance of the grafted MN, which expressed NT-3 high-affinity TrkC. The combination of MN implantation and EA application improved cortical motor-evoked potential relay and facilitated the locomotor performance of the paralyzed hindlimb compared with those of controls. These results suggest that the MN was better integrated into the host spinal cord neural network after EA treatment compared with control treatment. CONCLUSIONS: Electroacupuncture as an adjuvant therapy for TrkC-modified MSC-derived MN, acted by increasing the local production of NT-3, which accelerated neural network reconstruction and restoration of spinal cord function following SCI.

Schwann cell remyelination of the central nervous system: why does it happen and what are the benefits?

Myelin sheaths, by supporting axonal integrity and allowing rapid saltatory impulse conduction, are of fundamental importance for neuronal function. In response to demyelinating injuries in the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) migrate to the lesion area, proliferate and differentiate into new oligodendrocytes that make new myelin sheaths. This process is termed remyelination. Under specific conditions, demyelinated axons in the CNS can also be remyelinated by Schwann cells (SCs), the myelinating cell of the peripheral nervous system. OPCs can be a major source of these CNS-resident SCs-a surprising finding given the distinct embryonic origins, and physiological compartmentalization of the peripheral and central nervous system. Although the mechanisms and cues governing OPC-to-SC differentiation remain largely undiscovered, it might nevertheless be an attractive target for promoting endogenous remyelination. This article will (i) review current knowledge on the origins of SCs in the CNS, with a particular focus on OPC to SC differentiation, (ii) discuss the necessary criteria for SC myelination in the CNS and (iii) highlight the potential of using SCs for myelin regeneration in the CNS.

Adipose tissue stem cells in peripheral nerve regeneration-In vitro and in vivo.

After peripheral nerve injury, Schwann cells (SCs) are crucially involved in several steps of the subsequent regenerative processes, such as the Wallerian degeneration. They promote lysis and phagocytosis of myelin, secrete numbers of neurotrophic factors and cytokines, and recruit macrophages for a biological debridement. However, nerve injuries with a defect size of >1 cm do not show proper tissue regeneration and require a surgical nerve gap reconstruction. To find a sufficient alternative to the current gold standard-the autologous nerve transplant-several cell-based therapies have been developed and were experimentally investigated. One approach aims on the use of adipose tissue stem cells (ASCs). These are multipotent mesenchymal stromal cells that can differentiate into multiple phenotypes along the mesodermal lineage, such as osteoblasts, chondrocytes, and myocytes. Furthermore, ASCs also possess neurotrophic features, that is, they secrete neurotrophic factors like the nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, ciliary neurotrophic factor, glial cell-derived neurotrophic factor, and artemin. They can also differentiate into the so-called Schwann cell-like cells (SCLCs). These cells share features with naturally occurring SCs, as they also promote nerve regeneration in the periphery. This review gives a comprehensive overview of the use of ASCs in peripheral nerve regeneration and peripheral nerve tissue engineering both in vitro and in vivo. While the sustainability of differentiation of ASCs to SCLCs in vivo is still questionable, ASCs used with different nerve conduits, such as hydrogels or silk fibers, have been shown to promote nerve regeneration.

Management of urinary and bowel dysfunction in rabbit model of spinal cord injury using Schwann cells and muscle progenitors: functional study and evidence for novel mechanism of action.

PURPOSE: We tried to investigate the role of Schwann and satellite cells in the treatment of neurogenic bladder and bowel dysfunction; following spinal cord injury in the rabbit model. METHODS: Twelve male New Zealand rabbits underwent induction of neurogenic bladder by spinal cord injury. Rabbits underwent the fiber tractography analysis to confirm the induction of spinal cord injury. Then, animals were randomly divided into two groups. In group I (n = 4), Schwann cells were obtained from autologous peroneal nerve. In group II (n = 4), the co-culture of nerve-muscle cells was obtained from autologous peroneal nerve and quadriceps muscle. Animals in the control group (n = 4) did not undergo any rehabilitation therapy. One and 4 months after injection of cells into the external anal sphincter, electromyography, urethral pressure profiles, urodynamic studies, voiding cystourethrogram, and manometry was performed to confirm the efficacy of treatment in short- (1 month) and long-term (4 months) follow-ups. RESULTS: The investigations validated that no statistically significant difference was detected between the two experimental groups in a short-term follow-up (p-value > 0.05). However, the functional features were improved in group II in long-term follow-up. In both groups, the external anal sphincter contracted in response to electrical signals delivered to the muscle. However, more signals were detected in group II in electromyography evaluation. The immunohistochemical staining demonstrated that the histological features of the bladder and spinal cord were more satisfactory in group II in all follow-ups compared to group I, in terms of less edema, inflammation, presence of progenitor cells, and expression of muscle and nerve markes. CONCLUSION: Our results suggested that the injection of nerve-muscle co-culture cells into the external anal sphincter may be a helpful tactic for ameliorating the urological complications; following spinal cord injury induction in the rabbit model.