Promotes Schwann Cell Migration Research Articles

Acetyl-11-keto-beta-boswellic acid modulates macrophage polarization and Schwann cell migration to accelerate spinal cord injury repair in rats.

Inhibiting secondary inflammatory damage caused by glial cells and creating a stable microenvironment is one of the main strategies to investigate drugs for the treatment of spinal cord injury. Acetyl-11-keto-beta-boswellic acid (AKBA) is the active component of the natural drug boswellia, which has anti-inflammatory and antioxidant effects and offers a possible therapeutic option for spinal cord injury. In this study, a spinal cord injury model was established by crushing spinal cord, respectively, to detect the M1 macrophage inflammatory markers: iNOS, TNF-α, IL-1β, and the M2 macrophage markers CD206, ARG-1, IL-10, and the detection of antioxidant enzymes and MDA. Invitro, macrophages were cultured to verify the main mechanism of the macrophage switch from Nrf2/HO-1 to M2 type by flow cytometry, immunofluorescence, and other techniques. Macrophage and Schwann cell co-culture validated the migration mechanism of Schwann cells promoted by AKBA. AKBA significantly enhanced the antioxidant enzyme activities of CAT, GSH-Px, T-AOC, and SOD, reduced MDA content, and reduced oxidative damage caused by spinal cord injury via the Nrf2/HO-1 signaling pathway; AKBA mediates Nrf2/HO-1/IL-10, converts macrophages from M1 to M2 type, reduces inflammation, and promotes Schwann cell migration, thereby accelerating the repair of spinal cord injury in rats. Our work demonstrates that AKBA can attenuate oxidative stress as well as the secondary inflammatory injury caused by macrophages after SCI, promote Schwann cell migration to the injury site, and thus accelerate the repair of the injured spinal cord.

Axon-derived PACSIN1 binds to the Schwann cell survival receptor, LRP1, and transactivates TrkC to promote gliatrophic activities.

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following PNS injury. The ligands and receptors that activate and sustain SC transformation remain incompletely understood. Proteins released by injured axons represent important candidates for activating the SC Repair Program. The low-density lipoprotein receptor-related protein-1 (LRP1) is acutely up-regulated in SCs in response to injury, activating c-Jun, and promoting SC survival. To identify novel LRP1 ligands released in PNS injury, we applied a discovery-based approach in which extracellular proteins in the injured nerve were captured using Fc-fusion proteins containing the ligand-binding motifs of LRP1 (CCR2 and CCR4). An intracellular neuron-specific protein, Protein Kinase C and Casein Kinase Substrate in Neurons (PACSIN1) was identified and validated as an LRP1 ligand. Recombinant PACSIN1 activated c-Jun and ERK1/2 in cultured SCs. Silencing Lrp1 or inhibiting the LRP1 cell-signaling co-receptor, the NMDA-R, blocked the effects of PACSIN1 on c-Jun and ERK1/2 phosphorylation. Intraneural injection of PACSIN1 into crush-injured sciatic nerves activated c-Jun in wild-type mice, but not in mice in which Lrp1 is conditionally deleted in SCs. Transcriptome profiling of SCs revealed that PACSIN1 mediates gene expression events consistent with transformation to the repair phenotype. PACSIN1 promoted SC migration and viability following the TNFα challenge. When Src family kinases were pharmacologically inhibited or the receptor tyrosine kinase, TrkC, was genetically silenced or pharmacologically inhibited, PACSIN1 failed to induce cell signaling and prevent SC death. Collectively, these studies demonstrate that PACSIN1 is a novel axon-derived LRP1 ligand that activates SC repair signaling by transactivating TrkC.

Runx2 regulates peripheral nerve regeneration to promote Schwann cell migration and re-myelination.

Abstract JOURNAL/nrgr/04.03/01300535-202407000-00038/figure1/v/2023-11-20T171125Z/r/image-tiff Runx2 is a major regulator of osteoblast differentiation and function; however, the role of Runx2 in peripheral nerve repair is unclear. Here, we analyzed Runx2 expression following injury and found that it was specifically up-regulated in Schwann cells. Furthermore, using Schwann cell-specific Runx2 knockout mice, we studied peripheral nerve development and regeneration and found that multiple steps in the regeneration process following sciatic nerve injury were Runx2-dependent. Changes observed in Runx2 knockout mice include increased proliferation of Schwann cells, impaired Schwann cell migration and axonal regrowth, reduced re-myelination of axons, and a block in macrophage clearance in the late stage of regeneration. Taken together, our findings indicate that Runx2 is a key regulator of Schwann cell plasticity, and therefore peripheral nerve repair. Thus, our study shows that Runx2 plays a major role in Schwann cell migration, re-myelination, and peripheral nerve functional recovery following injury.

Regulation of Schwann cell proliferation and migration via miR-195-5p-induced Crebl2 downregulation upon peripheral nerve damage.

Schwann cells acquire a repair phenotype upon peripheral nerve injury (PNI), generating an optimal microenvironment that drives nerve repair. Multiple microRNAs (miRNAs) show differential expression in the damaged peripheral nerve, with critical regulatory functions in Schwann cell features. This study examined the time-dependent expression of miR-195-5p following PNI and demonstrated a marked dysregulation of miR-195-5p in the damaged sciatic nerve. CCK-8 and EdU assays were used to evaluate the effect of miR-195-5 on Schwann cell viability and proliferation. Schwann cell migration was tested using Transwell and wound healing assays. The miR-195-5p agomir injection experiment was used to evaluate the function of miR-195-5p in vivo. The potential regulators and effects of miR-195-5p were identified through bioinformatics evaluation. The relationship between miR-195-5p and its target was tested using double fluorescence reporter gene analysis. In Schwann cells, high levels of miR-195-5p decreased viability and proliferation, while suppressed levels had the opposite effects. However, elevated miR-195-5p promoted Schwann cell migration determined by the Transwell and wound healing assays. In vivo injection of miR-195-5p agomir into rat sciatic nerves promote axon elongation after peripheral nerve injury by affecting Schwann cell distribution and myelin preservation. Bioinformatic assessment further revealed potential regulators and effectors for miR-195-5p, which were utilized to build a miR-195-5p-centered competing endogenous RNA network. Furthermore, miR-195-5p directly targeted cAMP response element binding protein-like 2 (Crebl2) mRNA via its 3'-untranslated region (3'-UTR) and downregulated Crebl2. Mechanistically, miR-195-5p modulated Schwann cell functions by repressing Crebl2. The above findings suggested a vital role for miR-195-5p/Crebl2 in the regulation of Schwann cell phenotype after sciatic nerve damage, which may contribute to peripheral nerve regeneration.

α7 Nicotinic Acetylcholine Receptors May Improve Schwann Cell Regenerating Potential via Metabotropic Signaling Pathways.

Schwann cells (SCs) are glial cells involved in peripheral axon myelination. SCs also play a strategic role after peripheral nerve injury, regulating local inflammation and axon regeneration. Our previous studies demonstrated the presence of cholinergic receptors in SCs. In particular, the α7 nicotinic acetylcholine receptors (nAChRs) are expressed in SCs after peripheral axotomy, suggesting their involvement in the regulation of SC-regenerating properties. To clarify the role that α7 nAChRs may play after peripheral axon damage, in this study we investigated the signal transduction pathways triggered by receptor activation and the effects produced by their activation. Both ionotropic and metabotropic cholinergic signaling were analyzed by calcium imaging and Western blot analysis, respectively, following α7 nAChR activation. In addition, the expression of c-Jun and α7 nAChRs was evaluated by immunocytochemistry and Western blot analysis. Finally, the cell migration was studied by a wound healing assay. Activation of α7 nAChRs, activated by the selective partial agonist ICH3, did not induce calcium mobilization but positively modulated the PI3K/AKT/mTORC1 axis. Activation of the mTORC1 complex was also supported by the up-regulated expression of its specific p-p70 S6KThr389 target. Moreover, up-regulation of p-AMPKThr172, a negative regulator of myelination, was also observed concomitantly to an increased nuclear accumulation of the transcription factor c-Jun. Cell migration and morphology analyses proved that α7 nAChR activation also promotes SC migration. Our data demonstrate that α7 nAChRs, expressed by SCs only after peripheral axon damage and/or in an inflammatory microenvironment, contribute to improve the SCs regenerating properties. Indeed, α7 nAChR stimulation leads to an upregulation of c-Jun expression and promotes Schwann cell migration by non-canonical pathways involving the mTORC1 activity.

Branched-chain aminotransferase 1 promotes Schwann cell migration and proliferation to accelerate facial nerve regeneration through the Twist/FoxC1 and Sox2 pathways

Facial paralysis caused by injury to the facial nerve is common clinical presentation resulting in significant physical and psychological damage. In addition, due to the lack of understanding about the mechanisms of injury and repair and the lack of effective treatment targets, the clinical treatment outcomes for such patients remain poor. Schwann cells (SCs) have a central role in the regeneration of nerve myelin. In a rat model of facial nerves crush injury, we found that branched-chain aminotransferase 1 (BCAT1) was upregulated after injury. Moreover, it had a positive role in nerve repair. Using intervention methods such as gene knockdown, overexpression, and protein-specific inhibitors, combined with detection methods such as CCK8, Transwell, EdU, and flow cytometry, we demonstrated that BCAT1 significantly enhanced the migration and proliferation of SCs. It affected SC cell migration by regulating the Twist/Foxc1 signal axis and promoted cell proliferation by directly regulating the expression of SOX2. Similarly, animal experiments demonstrated that BCAT1 promotes facial nerve repair, improving nerve function and myelin regeneration by activating both the Twist/Foxc1 and SOX2 axes. In sum, BCAT1 promotes SC migration and proliferation, suggesting its potential as a key molecular target for improving the outcome of facial nerve injury repairs.

Sox2ot /miR-9 /Cthrc1 Promote Proliferation and Migration of Schwann Cells Following Nerve Injury

The effects of traditional treatments for peripheral nerve injury (PNI) are not ideal, which has prompted the identification of new therapeutic strategies. As unique glial cells in the peripheral nervous system, Schwann cells (SCs) play an important role in the repair of PNI. Recent studies have demonstrated that long noncoding RNAs (lncRNAs) are involved in the regulation of nerve repair after PNI. In this study, we used microarray technology to detect mRNA and lncRNA expression profiles at different time points after PNI and identified lncRNA Sox2ot-miR-9-Cthrc1 as a competitive endogenous RNA (ceRNA) for further investigation. Expression of lncRNA Sox2ot was increased after PNI, and overexpression of Sox2ot promoted SCs migration and proliferation. Mechanistic analyses confirmed that Sox2ot can regulate the expression of Cthrc1 through competitive adsorption of miR-9 in SCs, ultimately affecting SCs migration and proliferation. Our findings reveal the key role of lncRNA Sox2ot in nerve regeneration and provide a new direction for PNI treatment.

Bone Marrow Derived Cells Mediated Regulation of Schwann Cells Proliferation and Migration In vitro

Schwann cells (SCs) are the unique glial cells in the peripheral nerve. After peripheral nerve injury, SCs change their morphology, function, and play a new role as repair cells, through this process, factors that enhance SCs proliferation and promote SCs migration will benefit nerve regeneration and functional recovery. Bone marrow-derived cells (BMDCs), which has been proved to offer several regenerative benefits for tissue and organ injuries. However, whether BMDCs support nerve regeneration by affect the proliferation and migration of SCs, remains unclear. Here, we taken BMDCs co-cultured with nerve segments, and then investigated the proliferation and migration of SCs In vitro. Results demonstrated that BMDCs can enhance the proliferation of SCs, and then promoted SCs migration, forming Bungner’s brand-liked structure In vitro. These finding provide a potential new method for repair of injured peripheral nerves in clinical.

MiR-328a-3p modulates the proliferative and migratory abilities of Schwann cells in peripheral nerves

MicroRNAs (miRNAs) modulate Schwann cell phenotype. Here miR-328a-3p amounts after peripheral nerve damage were determined in injury stumps of the sciatic nerve in rats administered surgical crush. Quantitative real-time reverse transcription-polymerase chain reaction was performed to assess miR-328a-3p levels 0, 1, 4, 7 and 14 days post-sciatic nerve damage. The results showed miR-328a-3p was upregulated after nerve damage. CCK8 and EdU assays revealed elevated miR-328a-3p amounts suppressed Schwann cell viability and proliferation, respectively. Next, the migratory potential of cells was assessed by the Transwell chamber and wound healing assays. We found elevated miR-328a-3p amounts also suppressed Schwann cell migration. Conversely, low miR-328a-3p amounts promoted Schwann cell migration. The possible miR-328a-3p targets were predicted by bioinformatics. The 15 target genes retrieved provided insights into miR-328a-3p’s effects on Schwann cells and expanded the understanding of miR-328a-3p’s biological functions in the peripheral nervous system. Collectively, these findings revealed miR-328a-3p’s effects on Schwann cells and provided further insights into the functions of miRNAs in peripheral nerves.

Elevated matrix metalloproteinase 9 supports peripheral nerve regeneration via promoting Schwann cell migration

Matrix metalloproteinases (MMPs) are important contributing factors of tissue remodeling and wound healing. MMP9, a predominant soluble MMP, has been discovered as one of the most up-regulated genes in peripheral nerves after nerve injury, implying the potential regulatory roles of MMP9 during peripheral nerve regeneration. Considering that Schwann cell is a main cell population in peripheral nerves and MMP9 is secreted by Schwann cells, here, we investigated the biological functions of MMP9 on Schwann cell phenotype modulation. MMP9 gene knockdown or MMP9 recombinant protein exposure significantly hinders or elevates the migration ability of cultured Schwann cells, respectively. Direct application of MMP9 recombinant protein to sciatic nerve injured rats promotes Schwann cell migration, blood vessel formation, axon elongation, and myelin wrapping. Genetic exploration of MMP9-induced changes indicates that MMP9 regulates the extracellular region as well as the intracellular metabolism of Schwann cells. Our present study illuminates the importance of elevated MMP9 after nerve injury from the functional aspect and enhances our comprehension of the mechanisms underlying peripheral nerve regeneration.

Efficacy of sliced nerves of different thickness in a biodegradable nerve conduit to promote Schwann cell migration and axonal growth: An experimental study in the rat model.

Using the rat sciatic nerve model, sliced nerves of different thickness was combined to a biodegradable nerve conduit and the amount of nerve fragment necessary to promote nerve regeneration was investigated. Harvested sciatic nerve (n=6) was processed in sliced nerve of the different width; 2, 1, 0.5 mm, respectively. Western blot analysis was carried out to determine protein expression of Erk1/2. Subsequently, a total of 246 rats were used to create a 10 mm gap in the sciatic nerve. A polyglycolic acid-based nerve conduit was used to bridge the gap, with one sliced (width; 2, 1, 0.5 mm) or two (width; 1 mm × 2) incorporated within the conduit (n=6 at each point in each group). At 2, 4, 8, and 20 weeks after surgery, samples were resected and subjected to immune-histological, transmission electron microscopic, and motor functional evaluation for nerve regeneration. Western blot analysis demonstrated Erk1/2 expressions were significantly increased in the groups of 2-mm and 1-mm width and attenuated in the 0.5-mm width group (p < .05). The immune-histological study showed the migration of Schwann cells and axon elongation were significantly extended in the groups of 2-mm, 1-mm, and 1 mm × 2 width at 4 weeks (p < .01), in which nerve conduction velocity was marked at 20 weeks (p < .01) after implantation. When nerve tissue was inserted in the biodegradable nerve conduit as a sliced nerve, the method of inserting two sheets with a slice width of 1 mm most strongly accelerated motor function.

Leukemia inhibitory factor regulates Schwann cell proliferation and migration and affects peripheral nerve regeneration

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that stimulates neuronal development and survival. Our previous study has demonstrated that LIF mRNA is dysregulated in the peripheral nerve segments after nerve injury. Here, we show that LIF protein is abundantly expressed in Schwann cells after rat sciatic nerve injury. Functionally, suppressed or elevated LIF increases or decreases the proliferation rate and migration ability of Schwann cells, respectively. Morphological observations demonstrate that in vivo application of siRNA against LIF after peripheral nerve injury promotes Schwann cell migration and proliferation, axon elongation, and myelin formation. Electrophysiological and behavior assessments disclose that knockdown of LIF benefits the function recovery of injured peripheral nerves. Differentially expressed LIF affects the metabolism of Schwann cells and negatively regulates ERFE (Erythroferrone). Collectively, our observations reveal the essential roles for LIF in regulating the proliferation and migration of Schwann cells and the regeneration of injured peripheral nerves, discover ERFE as a downstream effector of LIF, and extend our understanding of the molecular mechanisms underlying peripheral nerve regeneration.

Overexpression of Foxc1 regenerates crushed rat facial nerves by promoting Schwann cells migration via the Wnt/β-catenin signaling pathway.

Facial paralysis can result in severe implications for patients. A good prognosis depends on the degree of nerve regeneration. Schwann cells (SCs) play an important role in facial nerve development and regeneration through migration. Forkhead box C1 (Foxc1), a member of the forkhead transcription factor family, is implicated in cell migration. However, the role of Foxc1 in the progression after facial nerve crush remains unknown. Our aim was to evaluate the effect of Foxc1 overexpression on SC migration and recovery of facial nerves after crush injury. The rat facial nerve crush injury model was established through the use of unilateral surgery. The results showed that the expression of Foxc1 was increased in the surgery group compared to that of the control group. SCs were isolated from the sciatic nerves and cultured. Foxc1, delivered by an adeno‐associated virus in vivo, or adenovirus in vitro, both induced overexpression of Foxc1, and increased the expression of CXCL12 and β‐catenin. After the transfection of Foxc1, the migration of SC was increased both in vitro and in vivo, was reduced by the inhibition of CXCL12 or β‐catenin. The facial nerve function and the nerve axon remyelination of the rats transfected with Foxc1 were significantly improved after nerve crush injury. Overall, the results demonstrated that overexpression of Foxc1 promoted SC migration by regulating CXCL12 via the Wnt/β‐catenin pathway, thus contributing to improved facial nerve function after crush injury.

Matrix metalloproteinase 7 promoted Schwann cell migration and myelination after rat sciatic nerve injury

Schwann cells experience de-differentiation, proliferation, migration, re-differentiation and myelination, and participate in the repair and regeneration of injured peripheral nerves. Our previous sequencing analysis suggested that the gene expression level of matrix metalloproteinase 7 (MMP7), a Schwann cell-secreted proteolytic enzyme, was robustly elevated in rat sciatic nerve segments after nerve injury. However, the biological roles of MMP7 are poorly understood. Here, we exposed primary cultured Schwann cells with MMP7 recombinant protein and transfected siRNA against MMP7 into Schwann cells to examine the effect of exogenous and endogenous MMP7. Meanwhile, the effects of MMP7 in nerve regeneration after sciatic nerve crush in vivo were observed. Furthermore, RNA sequencing and bioinformatic analysis of Schwann cells were conducted to show the molecular mechanism behind the phenomenon. In vitro studies showed that MMP7 significantly elevated the migration rate of Schwann cells but did not affect the proliferation rate of Schwann cells. In vivo studies demonstrated that increased level of MMP7 contributed to Schwann cell migration and myelin sheaths formation after peripheral nerve injury. MMP7-mediated genetic changes were revealed by sequencing and bioinformatic analysis. Taken together, our current study demonstrated the promoting effect of MMP7 on Schwann cell migration and peripheral nerve regeneration, benefited the understanding of cellular and molecular mechanisms underlying peripheral nerve injury, and thus might facilitate the treatment of peripheral nerve regeneration in clinic.

LncRNA BC088259 promotes Schwann cell migration through Vimentin following peripheral nerve injury.

Schwann cell, the major glial cell in the peripheral nervous system, plays an essential role in peripheral nerve regeneration. However, the regulation of Schwann cell behavior following nerve injury is insufficiently explored. According to the development of high-throughput techniques, long noncoding RNAs (lncRNAs) have been recognized. Accumulating evidence shows that lncRNAs take part in diverse biological processes and diseases. Here, by microarray analysis, we identified an upregulated lncRNA profile following sciatic nerve injury and focused on BC088259 for further investigation. Silencing or overexpression of BC088259 could affect Schwann cell migration. Mechanistically, BC088259 might exert this regulatory role by directly binding with Vimentin. Collectively, our study not only revealed a set of upregulated lncRNAs following nerve injury but also identified a new functional lncRNA, BC088259, which was important for Schwann cell migration, providing a therapeutic avenue toward peripheral nerve injury.

Bionanotube/Poly(3,4-ethylenedioxythiophene) Nanohybrid as an Electrode for the Neural Interface and Dopamine Sensor.

Poly(3,4-ethylene dioxythiophene) (PEDOT) is a promising conductive material widely used for interfacing with tissues in biomedical fields because of its unique properties. However, obtaining high charge injection capability and high stability remains challenging. In this study, pristine carbon nanotubes (CNTs) modified by dopamine (DA) self-polymerization on the surface polydopamine (PDA@CNTs) were utilized as dopants of PEDOT to prepare hybrid films through electrochemical deposition on the indium tin oxide (ITO) electrode. The PDA@CNTs-PEDOT film of the nanotube network topography exhibited excellent stability and strong adhesion to the ITO substrate compared with PEDOT and PEDOT/ p-toulene sulfonate. The PDA@CNTs-PEDOT-coated ITO electrodes demonstrated lower impedance and enhanced charge storage capacity than the bare ITO. When applying exogenous electrical stimulation (ES), robust long neurites sprouted from the dorsal root ganglion (DRG) neurons cultured on the PDA@CNTs-PEDOT film. Moreover, ES promoted Schwann cell migration out from the DRG spheres and enhanced myelination. The PDA@CNTs-PEDOT film served as an excellent electrochemical sensor for the detection of DA in the presence of biomolecule interferences. Results would shed light into the advancement of conducting nanohybrids for applications in the multifunctional bioelectrode in neuroscience.

Conduits harnessing spatially controlled cell-secreted neurotrophic factors improve peripheral nerve regeneration

An essential structure in nerve regeneration within engineered conduits is the “nerve bridge” initiated by centrally migrating Schwann cells in response to chemokine gradients. Introducing exogenous cells secreting neurotrophic factors aims to augment this repair process, but conventional cell-seeding methods fail to produce a directional chemokine gradient. We report a versatile method to encapsulate cells within conduit walls, allowing for reproducible control of spatial distribution along the conduit. Conduits with stem cells encapsulated within the central third possessed markedly different cell distribution and retention over 6 weeks in vivo, compared to standard cell lumen injection. Such a construct promoted Schwann cell migration centrally, and at 16 weeks rats presented with significantly enhanced function and axonal myelination. The method of utilizing a spatially restricted cell secretome departs from traditional homogeneous cell loading, and presents new approaches for studying and maximizing the potential of cell application in peripheral nerve repair.

Achyranthes bidentata polypeptides promotes migration of Schwann cells via NOX4/DUOX2-dependent ROS production in rats

Achyranthes bidentata polypeptides (ABPP), an active polypeptides isolated from the aqueous extract of Achyranthes bidentata Blume, contributes to the regeneration of injured peripheral nerves by promoting migration of Schwann cells (SCs). In this study, we aimed to investigate the possible mechanism underlying the ABPP-induced migration of primary cultured rat SCs. Transwell migration assays indicated that ABPP promoted SCs migration in a concentration-dependent manner by inducing production of NADPH-oxidase (NOX)-derived reactive oxygen species (ROS). Inhibition of ROS production by NOXs inhibitor apocynin (APO) or diphenyleneiodonium (DPI) partially blocked ABPP-mediated SCs migration. Furthermore, by using real-time polymerase chain reaction analysis and siRNA interference technique, we verified the participation of NOX subunit 4 (NOX4) and dual oxidase 2 (DUOX2) in ABPP-induced ROS production and consequential SCs migration. Taken together, these results demonstrated that ABPP promoted SCs migration via NOX4/DUOX2-activated ROS in SCs.

In vitro and in vivo studies of electroactive reduced graphene oxide-modified nanofiber scaffolds for peripheral nerve regeneration

Graphene, as a promising biomaterial, has received great attention in biomedical fields due to its intriguing properties, especially the conductivity and biocompatibility. Given limited studies on the effects of graphene-based scaffolds on peripheral nerve regeneration in vitro and in vivo under electrical stimulation (ES), the present study was intended to systematically investigate how conductive graphene-based nanofibrous scaffolds regulate Schwann cell (SC) behavior including migration, proliferation and myelination, and PC12 cell differentiation in vitro via ES, and whether these conductive scaffolds could guide SC migration and promote nerve regeneration in vivo. Briefly, the reduced graphene oxide (RGO) was coated onto ApF/PLCL nanofibrous scaffolds via in situ redox reaction of the graphene oxide (GO). In vitro, RGO-coated ApF/PLCL (AP/RGO) scaffolds significantly enhanced SC migration, proliferation, and myelination including myelin-specific gene expression and neurotrophic factor secretion. The conditioned media of SCs cultured on AP/RGO scaffolds under ES could induce the differentiation of PC12 cells in a separate culture. In addition, PC12 cells cultured on the conductive AP/RGO scaffolds also showed elevated differentiation upon ES. In vivo implantation of the conductive AP/RGO nerve guidance conduits into rat sciatic nerve defects exhibited a similar healing capacity to autograft, which is the current gold standard in peripheral nerve regeneration. In view of the performance of AP/RGO scaffolds in modulating cell functions in vitro and promoting nerve regeneration in vivo, it is expected that the graphene-based conductive nanofibrous scaffolds would exhibit their potential in peripheral nerve repair and regeneration. Statement of significanceDespite the demonstrated capability of bridging the distal and proximal peripheral nerves, it remains a significant challenge with current artificial nerve conduits to achieve the desired physiological functions, e.g., the transmission of electrical stimuli. Herein, we explored the possibility of combining the conductive properties of graphene with electrospun nanofiber to create the electroactive biomimetic scaffolds for nerve tissue regeneration. In vitro and in vivo studies were carried out: (1) In vitro, the conductive nanofibrous scaffolds significantly promoted SC migration, proliferation and myelination including myelin specific gene expression and neurotrophicfactor secretion, and induced PC12 cell differentiation with electrical stimulation. (2) In vivo, the conductive nerve guidance conduit exhibited similar effects with the gold standard autograft. In view of the performance of this conductive scaffold in modulating the cell functions in vitro and promoting nerve regeneration in vivo, it is expected that the graphene-modified nanofibrous scaffolds will exhibit their potential in peripheral nerve repair and regeneration.

CXCL12 has therapeutic value in facial nerve injury and promotes Schwann cells autophagy and migration via PI3K-AKT-mTOR signal pathway

Facial nerve injury is a clinically common disease accompanied by demyelination of damaged nerves. The remyelination of damaged nerves and the unsatisfactory function recovery are problems that have been plaguing people for a long time. The role that CXCL12 plays after facial nerve injury remains unknown. Our experiments found that the expression of CXCL12 was up-regulated in the early stage of facial nerve injury and decreased after two weeks. Further research found that CXCL12 had no effect on Schwann cells proliferation, apoptosis and cell cycle, while significantly promoted Schwann cells migration. Treatment with CXCL12 decreased the phosphorylation of PI3K, AKT and mTOR, but increased autophagy marker LC3II/I. The CXCL12-induced Schwann cells migration was significantly attenuated by inhibition of autophagy and activation of PI3K pathway through pretreatment with 3-MA and IGF-1 respectively, and this effect was enhanced by PI3K pathway inhibitor LY294002. Animal experiment also confirmed that CXCL12 could improve facial nerve function and myelin regeneration. The findings of this study indicate that CXCL12 can promote the migration of Schwann cells and potentially become a key molecule in the repair of facial nerve injury.