Injured Peripheral Nerves Research Articles

Effects of regenerative peripheral nerve interface on dorsal root ganglia neurons following peripheral axotomy.

BackgroundLong-term delayed reconstruction of injured peripheral nerves always results in poor recovery. One important reason is retrograde cell death among injured sensory neurons of dorsal root ganglia (DRG). A regenerative peripheral nerve interface (RPNI) was capable of generating new synaptogenesis between the proximal nerve stump and free muscle graft. Meanwhile, sensory receptors within the skeletal muscle can also be readily reinnervated by donor sensory axons, which allows the target muscles to become sources of sensory information for function reconstruction. To date, the effect of RPNI on injured sensory neurons is still unclear. Here, we aim to investigate the potential neuroprotective role of RPNI on sensory DRG neurons after sciatic axotomy in adult rats.Materials and methodsThe sciatic nerves of sixty rats were transected. The rats were randomly divided into three groups following this nerve injury: no treatment (control group, n = 20), nerve stump implantation inside a fully innervated muscle (NSM group, n = 20), or nerve stump implantation inside a free muscle graft (RPNI group, n = 20). At 8 weeks post-axotomy, ipsilateral L4 and L5 DRGs were harvested in each group. Toluidine blue staining was employed to quantify the neuronal densities in DRGs. The neuronal apoptosis index was quantified with TUNEL assay. Western blotting was applied to measure the expressions of Bax, Bcl-2, and neurotrophins (NTs) in ipsilateral DRGs.ResultsThere were significantly higher densities of neurons in ipsilateral DRGs of RPNI group than NSM and control groups at 8 weeks post-axotomy (p < 0.01). Meanwhile, neuronal apoptosis index and the expressions of pro-apoptotic Bax within the ipsilateral DRGs were significantly lower in the RPNI group than those in the control and NSM groups (p < 0.05), while the opposite result was observed in the expression of pro-survival Bcl-2. Furthermore, the expressions of NGF, NT-3, BDNF, and GDNF were also upregulated in the ipsilateral DRGs in the RPNI group (p < 0.01).ConclusionThe present results demonstrate that RPNI could prevent neuronal loss after peripheral axotomy. And the neuroprotection effect has a relationship with the upregulation of NTs in DRGs, such as NGF, NT-3, BDNF, and GDNF. These findings provide an effective therapy for neuroprotection in the delayed repair of the peripheral nerve injury.

Causalgia: a military pain syndrome.

Causalgia, officially known as complex regional pain syndrome type II, is a pain syndrome characterized by severe burning pain, motor and sensory dysfunction, and changes in skin color and temperature sensation distal to an injured peripheral nerve. The pain syndrome primarily tends to affect combat soldiers after they sustain wartime injuries from blasts and gunshots. Here, the authors provide a historical narrative that showcases the critical contributions of military physicians to our understanding of causalgia and to the field of peripheral nerve neurosurgery as a whole.

Comparison of human skin- and nerve-derived Schwann cells reveals many similarities and subtle genomic and functional differences.

Skin is an easily accessible tissue and a rich source of Schwann cells (SCs). Toward potential clinical application of autologous SC therapies, we aim to improve the reliability and specificity of our protocol to obtain SCs from small skin samples. As well, to explore potential functional distinctions between skin-derived SCs (Sk-SCs) and nerve-derived SCs (N-SCs), we used single-cell RNA-sequencing and a series of in vitro and in vivo assays. Our results showed that Sk-SCs expressed typical SC markers. Single-cell sequencing of Sk- and N-SCs revealed an overwhelming overlap in gene expression with the exception of HLA genes which were preferentially up-regulated in Sk-SCs. In vitro, both cell types exhibited similar levels of proliferation, migration, uptake of myelin debris and readily associated with neurites when co-cultured with human iPSC-induced motor neurons. Both exhibited ensheathment of multiple neurites and early phase of myelination, especially in N-SCs. Interestingly, dorsal root ganglion (DRG) neurite outgrowth assay showed substantially more complexed neurite outgrowth in DRGs exposed to Sk-SC conditioned media compared to those from N-SCs. Multiplex ELISA array revealed shared growth factor profiles, but Sk-SCs expressed a higher level of VEGF. Transplantation of Sk- and N-SCs into injured peripheral nerve in nude rats and NOD-SCID mice showed close association of both SCs to regenerating axons. Myelination of rodent axons was observed infrequently by N-SCs, but absent in Sk-SC xenografts. Overall, our results showed that Sk-SCs share near-identical properties to N-SCs but with subtle differences that could potentially enhance their therapeutic utility.

Low-Stiffness Hydrogels Promote Peripheral Nerve Regeneration Through the Rapid Release of Exosomes.

A hydrogel system loaded with mesenchymal stem cell–derived exosome (MSC-Exos) is an attractive new tool for tissue regeneration. However, the effect of the stiffness of exosome-loaded hydrogels on tissue regeneration is unclear. Here, the role of exosome-loaded hydrogel stiffness, during the regeneration of injured nerves, was assessed in vivo. The results showed that the photocrosslinkable hyaluronic acid methacrylate hydrogel stiffness plays an important role in repairing nerve injury. Compared with the stiff hydrogels loaded with exosomes, soft hydrogels loaded with exosomes showed better repair of injured peripheral nerves. The soft hydrogel promoted nerve repair by quickly releasing exosomes to inhibit the infiltration of macrophages and the expression of the proinflammatory factors IL-1β and TNF-α in injured nerves. Our work revealed that exosome-loaded hydrogel stiffness plays an important role in tissue regeneration by regulating exosome release behavior and provided important clues for the clinical application of biological scaffold materials.

QS71. A Novel Biologic Nerve Interface for Exoskeleton Control in the Setting of Peripheral Nerve Compromise

Purpose: Advanced exoskeletons have been developed as assistive devices for those individuals with extremity weakness. Unfortunately, they are rarely utilized secondary to inadequate human-machine interfacing capabilities. To address this limitation, we have developed the Muscle Cuff Regenerative Peripheral Nerve Interface (MC-RPNI) which consists of a free skeletal muscle graft wrapped around an intact peripheral nerve. Over time, the MC-RPNI regenerates and becomes reinnervated and has the ability to amplify efferent motor action potentials to facilitate accurate and discrete exoskeleton control. The primary objective of this experiment was to determine if the MC-RPNI can amplify nerve signals in a nerve injury model without adversely impacting the function of distally-innervated muscles. Methods: Rats were randomly assigned to five groups (n=6/group): (1) MC-RPNI; (2) nerve injury with distal MC-RPNI; (3) nerve injury with proximal MC-RPNI; (4) nerve injury; and (5) sham. Nerve injuries were created by resecting 50% of the common peroneal nerve’s diameter over a length of 15mm. MC-RPNIs were fabricated by harvesting and trimming the contralateral extensor digitorum longus (EDL) muscle to a length of 10mm and securing it to the nerve circumferentially with sutures. The MC-RPNI was placed distal (Group 2) or proximal (Group 3) to the nerve injury or centrally (Group 1) on the peroneal nerve. At three months, rats underwent electrophysiological analysis and muscle-force testing. Results: All MC-RPNIs remained viable and demonstrated appropriate regeneration and reinnervation on histology and IHC. Peroneal nerve motor action potential amplitudes measured 71.8+/-18.3µV for injured nerves and 120.1+/-17.6µV for intact nerves. Average CMAPs were 5.1+/-0.8mV in MC-RPNIs located proximal to the nerve-injury and 2.9+/-0.4mV in those located distally, producing signal amplification of 38x and 53x, respectively. Although the MC-RPNI had no impact on distal muscle function in non-nerve-injured groups (EDL maximal tetanus: controls=2900+/-118mN; MC-RPNIs=2658+/-166mN), its location in rats with nerve-injury did have an effect. For those with the MC-RPNI located distally, EDL maximal tetanus (2223.9+/-201.5mN) was similar to those obtained from nerve-injury only rats (1932.2+/-96.0mN). However, for those rats with the MC-RPNI placed proximally, maximal tetanus (1233.2+/-184.7mN) was significantly lower. Conclusion: When placed distal to nerve injury, the MC-RPNI has the ability to amplify injured peripheral nerve signals by several magnitudes while avoiding further functional impairment of distally-innervated muscle. However, muscle impairment can result if the MC-RPNI is placed proximal to a nerve-injury. Thus, it is important to consider the location of the nerve-injury when designing MC-RPNI interventions for the control of exoskeleton devices.

Reduced graphene oxide-embedded nerve conduits loaded with bone marrow mesenchymal stem cell-derived extracellular vesicles promote peripheral nerve regeneration

We previously combined reduced graphene oxide (rGO) with gelatin-methacryloyl (GelMA) and polycaprolactone (PCL) to create an rGO-GelMA-PCL nerve conduit and found that the conductivity and biocompatibility were improved. However, the rGO-GelMA-PCL nerve conduits differed greatly from autologous nerve transplants in their ability to promote the regeneration of injured peripheral nerves and axonal sprouting. Extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSCs) can be loaded into rGO-GelMA-PCL nerve conduits for repair of rat sciatic nerve injury because they can promote angiogenesis at the injured site. In this study, 12 weeks after surgery, sciatic nerve function was measured by electrophysiology and sciatic nerve function index, and myelin sheath and axon regeneration were observed by electron microscopy, immunohistochemistry, and immunofluorescence. The regeneration of microvessel was observed by immunofluorescence. Our results showed that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived extracellular vesicles were superior to rGO-GelMA-PCL conduits alone in their ability to increase the number of newly formed vessels and axonal sprouts at the injury site as well as the recovery of neurological function. These findings indicate that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived extracellular vesicles can promote peripheral nerve regeneration and neurological function recovery, and provide a new direction for the curation of peripheral nerve defect in the clinic.

Based on proteomics to explore the mechanism of mecobalamin promoting the repair of injured peripheral nerves.

Mecobalamin is commonly used in the adjuvant intervention of various peripheral nerve injuries. Actin cytoskeleton plays a role in the regeneration of myelin and axon. Therefore, the purpose of this study was to explore the possibility of mecobalamin regulating actin cytoskeleton in repairing nerve injury. In this study, a crush injury on the right sciatic nerve of two groups of rats (12 in each group) was established. The control group was only given normal saline (i.g.), and the intervention group was given mecobalamin 1mg/kg(i.g.).Theratswere sacrificed on 28th day and the injured nerves were collected for proteomics. The result shows that regulation of actin cytoskeleton pathway changed significantly. The expression of protein Vav1 was verified by Western blot and immunofluorescence. In the intervention group, the nerve fiber structure was complete, the axons were dense and symmetrical, and the myelin sheath was compact and uniform in thickness. The positive rate of myelin basic protein and βⅢ-tubulin was higher than that in the control group. The findings of the study show that mecobalamin regulates the actin cytoskeleton in the repair of nerve damage and upregulates Vav1 in the regulation of actin cytoskeleton pathway.

Highly Stretchable Hydrogels as Wearable and Implantable Sensors for Recording Physiological and Brain Neural Signals.

Recording electrophysiological information such as brain neural signals is of great importance in health monitoring and disease diagnosis. However, foreign body response and performance loss over time are major challenges stemming from the chemomechanical mismatch between sensors and tissues. Herein, microgels are utilized as large crosslinking centers in hydrogel networks to modulate the tradeoff between modulus and fatigue resistance/stretchability for producing hydrogels that closely match chemomechanical properties of neural tissues. The hydrogels exhibit notably different characteristics compared to nanoparticles reinforced hydrogels. The hydrogels exhibit relatively low modulus, good stretchability, and outstanding fatigue resistance. It is demonstrated that the hydrogels are well suited for fashioning into wearable and implantable sensors that can obtain physiological pressure signals, record the local field potentials in rat brains, and transmit signals through the injured peripheral nerves of rats. The hydrogels exhibit good chemomechanical match to tissues, negligible foreign body response, and minimal signal attenuation over an extended time, and as such is successfully demonstrated for use as long‐term implantable sensory devices. This work facilitates a deeper understanding of biohybrid interfaces, while also advancing the technical design concepts for implantable neural probes that efficiently obtain physiological information.

Sustainable release of nerve growth factor for peripheral nerve regeneration using nerve conduits laden with Bioconjugated hyaluronic acid-chitosan hydrogel

Peripheral nerve regeneration following injury is often incomplete, resulting in significant personal and socioeconomic costs. Nerve conduits have been developed to complement or replace autologous nerve grafts. In this study, repairing injured peripheral nerves in rats is investigated by fabricating poly(D, l-lactic acid) (PDLLA)/β-tricalcium phosphate (β-TCP) nerve conduits filled by injectable chitosan (CS)-hyaluronic acid (HA) hydrogels featuring sustained release of nerve growth factor (NGF). All CS-HA hydrogels have porosities higher than 80%. The mass loss of the CS-HA hydrogels reaches 70% in 8 weeks. In vitro experiments suggest that the CS-HA/NGF hydrogels are suitable for the adhesion, spreading, and differentiation of neuronal cells, which also allow for sustained release of NGF. In vivo studies on the repair of 10-mm sciatic nerve defects in rats are used to assess nerve repair rate through walking track analysis, gastrocnemius weight analysis, and histological analysis. It is shown that the PDLLA/β-TCP nerve conduits laden with CS-HA/NGF hydrogels have a significant positive effect on the axon regeneration and myelination, compared to the PDLLA/β-TCP hollow nerve conduits and the autograft group. These results show that the CS-HA/NGF injectable hydrogel can effectively promote nerve regeneration making it a good candidate in the field of neural tissue engineering.

Comparison of Collagen and Human Amniotic Membrane Nerve Wraps and Conduits for Peripheral Nerve Repair in Preclinical Models: A Systematic Review of the Literature.

Collagen and human amniotic membrane (hAM) are Food and Drug Administration (FDA)-approved biomaterials that can be used as nerve wraps or conduits for repair of peripheral nerve injuries. Both biomaterials have been shown to reduce scarring and fibrosis of injured peripheral nerves. However, comparative advantages and disadvantages have not been definitively shown in the literature. The purpose of this systematic review is to comprehensively evaluate the literature regarding the roles of hAM and collagen nerve wraps and conduits on peripheral nerve regeneration in preclinical models. The MEDLINE database was queried using the PubMed search engine on July 7, 2019, with the following search strategy: ("amniotic membrane" OR "amnion") OR ("collagen conduit" OR "nerve wrap")] AND "nerve." All resulting articles were screened by two independent reviewers. Nerve type, lesion type/injury model, repair type, treatment, and outcomes were assessed. Two hundred and fifty-eight articles were identified, and 44 studies remained after application of inclusion and exclusion criteria. Seventeen studies utilized hAM, whereas 27 studies utilized collagen wraps or conduits. Twenty-three (85%) of the collagen studies utilized conduits, and four (15%) utilized wraps. Six (35%) of the hAM studies utilized conduits and 11 (65%) utilized wraps. Two (9%) collagen studies involving a conduit and one (25%) involving a wrap demonstrated at least one significant improvement in outcomes compared with a control. While none of the hAM conduit studies showed significant improvements, eight (73%) of the studies investigating hAM wraps showed at least one significant improvement in outcomes. The majority of studies reported positive outcomes, indicating that collagen and hAM nerve wraps and conduits both have the potential to enhance peripheral nerve regeneration. However, relatively few studies reported significant findings, except for studies evaluating hAM wraps. Preclinical models may help guide clinical practice regarding applications of these biomaterials in peripheral nerve repair.

Fabrication of a 3D Printed PCL Nerve Guide: In Vitro and In Vivo Testing.

Nerve guides are medical devices designed to guide proximal and distal ends of injured peripheral nerves in order to assist regeneration of the damaged nerves. A 3D-printed polycaprolactone (PCL) nerve guide using an aligned gelatin-poly(3-hydroxybutyrate-co-3-hydroxyvalerate) electrospun mat, seeded with PC12 and Schwann cells (SCs) is produced. During characterization with microCT and SEM porosity (55%), pore sizes (675± 40µm), and fiber diameters (382± 25µm) are determined. Electrospun fibers have degree of alignment of 7°, indicating high potential for guidance. On Day 14, PC12 cells migrated from proximal to distal end of nerve guide when SCs are seeded on the guide. After 28 days, over 95% of PC12 are alive and aligned. PC12 cells express early differentiation marker beta-tubulin 10 times more than late marker NeuN. In a 10mm rat sciatic nerve injury, functional recovery evaluated by using static sciatic index (SSI) is observed in mat-free guides and guides containing mat and SCs. Nerve conduction velocities are also improved in these groups. Histological stainings showed tissue growth around nerve guides with highest new tissue organization being observed with mat and cell-free guides. These suggest 3D-printed PCL nerve guides have significant potential for treatment of peripheral nerve injuries.

Polydopamine-modified chitin conduits with sustained release of bioactive peptides enhance peripheral nerve regeneration in rats.

The introduction of neurotrophic factors into injured peripheral nerve sites is beneficial to peripheral nerve regeneration. However, neurotrophic factors are rapidly degraded in vivo and obstruct axonal regeneration when used at a supraphysiological dose, which limits their clinical benefits. Bioactive mimetic peptides have been developed to be used in place of neurotrophic factors because they have a similar mode of action to the original growth factors and can activate the equivalent receptors but have simplified sequences and structures. In this study, we created polydopamine-modified chitin conduits loaded with brain-derived neurotrophic factor mimetic peptides and vascular endothelial growth factor mimetic peptides (Chi/PDA-Ps). We found that the Chi/PDA-Ps conduits were less cytotoxic in vitro than chitin conduits alone and provided sustained release of functional peptides. In this study, we evaluated the biocompatibility of the Chi/PDA-Ps conduits. Brain-derived neurotrophic factor mimetic peptide and vascular endothelial growth factor mimetic peptide synergistically promoted proliferation of Schwann cells and secretion of neurotrophic factors by Schwann cells and attachment and migration of endothelial cells in vitro. The Chi/PDA-Ps conduits were used to bridge a 2 mm gap between the nerve stumps in rat models of sciatic nerve injury. We found that the application of Chi/PDA-Ps conduits could improve the motor function of rats and reduce gastrocnemius atrophy. The electrophysiological results and the microstructure of regenerative nerves showed that the nerve conduction function and remyelination was further restored. These findings suggest that the Chi/PDA-Ps conduits have great potential in peripheral nerve injury repair.

MiR-140-3p suppresses the proliferation and migration of macrophages.

Macrophages benefit myelin debris removal, blood vessel formation, and Schwann cell activation following peripheral nerve injury. Identifying factors that modulate macrophage phenotype may advantage the repair and regeneration of injured peripheral nerves. microRNAs (miRNAs) are important regulators of many physiological and pathological processes, including peripheral nerve regeneration. Herein, we investigated the regulatory roles of miR-140-3p, a miRNA that was differentially expressed in injured rat sciatic nerves, in macrophage RAW264.7 cells. Observations from EdU proliferation assay demonstrated that elevated miR-140-3p decreased the proliferation rates of RAW264.7 cells while suppressed miR-140-3p increased the proliferation rates of RAW264.7 cells. Transwell-based migration assay showed that up-regulated and down-regulated miR-140-3p led to elevated and reduced migration abilities, respectively. However, the abundances of numerous phenotypic markers of M1 and M2 macrophages were not significantly altered by miR-140-3p mimic or inhibitor transfection. Bioinformatic analysis and miR-140-3p-induced gene suppression examination suggested that Smad3 might be the target gene of miR-140-3p. These findings illuminate the inhibitory effects of miR-140-3p on the proliferation and migration of macrophages and contribute to the cognition of the essential roles of miRNAs during peripheral nerve regeneration.

Sustained release of exosomes loaded into polydopamine-modified chitin conduits promotes peripheral nerve regeneration in rats.

Exosomes derived from mesenchymal stem cells are of therapeutic interest because of their important role in intracellular communication and biological regulation. On the basis of previously studied nerve conduits, we designed a polydopamine-modified chitin conduit loaded with mesenchymal stem cell-derived exosomes that release the exosomes in a sustained and stable manner. In vitro experiments revealed that rat mesenchymal stem cell-derived exosomes enhanced Schwann cell proliferation and secretion of neurotrophic and growth factors, increased the expression of Jun and Sox2 genes, decreased the expression of Mbp and Krox20 genes in Schwann cells, and reprogrammed Schwann cells to a repair phenotype. Furthermore, mesenchymal stem cell-derived exosomes promoted neurite growth of dorsal root ganglia. The polydopamine-modified chitin conduits loaded with mesenchymal stem cell-derived exosomes were used to bridge 2 mm rat sciatic nerve defects. Sustained release of exosomes greatly accelerated nerve healing and improved nerve function. These findings confirm that sustained release of mesenchymal stem cell-derived exosomes loaded into polydopamine-modified chitin conduits promotes the functional recovery of injured peripheral nerves.

Dysregulated miR-29a-3p/PMP22 Modulates Schwann Cell Proliferation and Migration During Peripheral Nerve Regeneration.

Schwann cells switch to a repair phenotype following peripheral nerve injury and create a favorable microenvironment to drive nerve repair. Many microRNAs (miRNAs) are differentially expressed in the injured peripheral nerves and play essential roles in regulating Schwann cell behaviors. Here, we examine the temporal expression patterns of miR-29a-3p after peripheral nerve injury and demonstrate significant up-regulation of miR-29a-3p in injured sciatic nerves. Elevated miR-29a-3p inhibits Schwann cell proliferation and migration, while suppressed miR-29a-3p executes reverse effects. In vivo injection of miR-29a-3p agomir to rat sciatic nerves hinders the proliferation and migration of Schwann cells, delays the elongation and myelination of axons, and retards the functional recovery of injured nerves. Mechanistically, miR-29a-3p modulates Schwann cell activities via negatively regulating peripheral myelin protein 22 (PMP22), and PMP22 extensively affects Schwann cell metabolism. Our results disclose the vital role of miR-29a-3p/PMP22 in regulating Schwann cell phenotype following sciatic nerve injury and shed light on the mechanistic basis of peripheral nerve regeneration.

Can Early Electrical Stimulation Accelerates the Neural Regeneration by Increasing the Expression of BDNF and GDNF in Distal Part of Injured Peripheral Nerve? An Animal Experimental Study

BACKGROUND: The role of neurotrophic factors (brain-derived neurotrophic factors and glial cell line-derived neurotrophic factors) and early electrical stimulation (EES) in the injured nerve has found promising in several studies. However, there is still limited knowledge about the effect of EES in the distal part of the nerve to sustain this level of expression of growth factors. AIM: We aim to evaluate the effects of EES in in neural regeneration by measuring the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in animal model. METHODS: The research was conducted starting from April to May 2021 using male Wistar rats. Using general anesthesia, the sciatic nerve was cut. The intervention group was treated with EES in the distal stump, right after nerve resection (20 Hz, 1–2 mA, 2–5 s), while the control group received no treatment after nerve resection. A reoperation on day 3 was performed in both groups to measure BDNF and GDNF expression level of the distal nerve tissue by ELISA as well as histopathological examination of sprouting axons of the injured proximal nerve. RESULTS: A total of 32 samples were included in the study. A statistically significant levels of GDNF is found higher in the EES group (n = 16) than the control group (n = 16) (35. 71 pg/100 mg, confidence interval (CI) 95% 23.93, 47.48, p &lt; 0.05). The number of sprouting axons is found lower in the EES group (p &lt; 0.05). The BDNF level is similar between the two groups, however not significant. After a subgroup analysis, it was found that the greater the level of GDNF, the fewer the axon sprouts in both groups (fewer axon group 58.35 [n = 22, CI 95% 45.14, 71.55] vs. more axon group 47.14 [n = 10, CI 95% 35.33, 58.95]), p &lt; 0.05. CONCLUSION: The EES proves its benefit in accelerating the axonal regeneration by increasing the expression GDNF in the distal nerve stumps in the electrical excited degenerated sciatic nerve in the rat model.

SIRT6 Negatively Regulates Schwann Cells Dedifferentiation via Targeting c-Jun During Wallerian Degeneration After Peripheral Nerve Injury.

Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Previous studies have been reported a pro-regenerative role of SIRT6 in central nervous system injury. However, the role of SIRT6 in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of SIRT6 steering Schwann cell dedifferentiation during Wallerian degeneration in injured peripheral nerve. Herein, we first examined the expression pattern of SIRT6 after peripheral nerve injury. Using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that SIRT6 inhibitor accelerates Schwann cell dedifferentiation as well as axonal and myelin degeneration, while SIRT6 activator attenuates this process. Moreover, in an in vitro Schwann cell dedifferentiation model, we found SIRT6 inhibitor promotes Schwann cell dedifferentiation through upregulating the expression of c-Jun. In addition, downregulation of c-Jun reverse the effects of SIRT6 inhibition on the Schwann cells dedifferentiation and axonal and myelin degeneration. In summary, we first described SIRT6 acts as a negative regulator for Schwann cells dedifferentiation during Wallerian degeneration and c-Jun worked as a direct downstream partner of SIRT6 in injured peripheral nerve.

Up-Regulation of CD146 in Schwann Cells Following Peripheral Nerve Injury Modulates Schwann Cell Function in Regeneration.

CD146 is cell adhesion molecule and is implicated in a variety of physiological and pathological processes. However, the involvement of CD146 in peripheral nerve regeneration has not been studied yet. Here, we examine the spatial and temporal expression pattern of CD146 in injured mouse sciatic nerve via high-throughput data analysis, RT-PCR and immunostaining. By microarray data analysis and RT-PCR validation, we show that CD146 mRNA is significantly up-regulated in the nerve bridge and in the distal nerve stump following mouse sciatic nerve transection injury. By single cell sequencing data analysis and immunostaining, we demonstrate that CD146 is up-regulated in Schwann cells and cells associated with blood vessels following mouse peripheral nerve injury. Bioinformatic analysis revealed that CD146 not only has a key role in promoting of blood vessel regeneration but also regulates cell migration. The biological function of CD146 in Schwann cells was further investigated by knockdown of CD146 in rat primary Schwann cells. Functional assessments showed that knockdown of CD146 decreases viability and proliferation of Schwann cells but increases Schwann cell migration. Collectively, our findings imply that CD146 could be a key cell adhesion molecule that is up-regulated in injured peripheral nerves to regulate peripheral nerve regeneration.

Neuroinflammation Mediates Faster Brachial Plexus Regeneration in Subjects with Cerebral Injury.

Our previous investigation suggested that faster seventh cervical nerve (C7) regeneration occurs in patients with cerebral injury undergoing contralateral C7 transfer. This finding needed further verification, and the mechanism remained largely unknown. Here, Tinel's test revealed faster C7 regeneration in patients with cerebral injury, which was further confirmed in mice by electrophysiological recordings and histological analysis. Furthermore, we identified an altered systemic inflammatory response that led to the transformation of macrophage polarization as a mechanism underlying the increased nerve regeneration in patients with cerebral injury. In mice, we showed that, as a contributing factor, serum amyloid protein A1 (SAA1) promoted C7 regeneration and interfered with macrophage polarization in vivo. Our results indicate that altered inflammation promotes the regenerative capacity of the C7 nerve by altering macrophage behavior. SAA1 may be a therapeutic target to improve the recovery of injured peripheral nerves.

Research Progress in the Repair of Peripheral Nerve Injury with Adipose-Derived Stem Cell Exosomes

The repair of peripheral nerve injury has always been a difficult clinical problem. Although a variety of treatment methods are available in clinical practice, their efficacy is limited. In recent years, the components carried by adipose stem cell exosomes and their functions have been increasingly discovered. A large number of experiments conducted around the world have shown that adipose-derived stem cell exosomes have a positive effect on the repair of peripheral nerve injury. This article reviews recent progress toward the use of adipose-derived stem cell exosomes in the repair of injured peripheral nerves and possible future research directions involving adipose-derived stem cell exosomes.