Peripheral glial Schwann cells switch to a repair state after nerve injury, proliferate to supply lost cell population, migrate to form regeneration tracks, and contribute to the generation of a permissive microenvironment for nerve regeneration. Exploring essential regulators of the repair responses of Schwann cells may benefit the clinical treatment for peripheral nerve injury. In the present study, we find that FOSL1, a AP-1 member that encodes transcription factor FOS Like 1, is highly expressed at the injured sites following peripheral nerve crush. Interfering FOSL1 decreases the proliferation rate and migration ability of Schwann cells, leading to impaired nerve regeneration. Mechanism investigations demonstrate that FOSL1 regulates Schwann cell proliferation and migration by directly binding to the promoter of EPH Receptor B2 (EPHB2) and promoting EPHB2 transcription. Collectively, our findings reveal the essential roles of FOSL1 in regulating the activation of Schwann cells and indicate that FOSL1 can be targeted as a novel therapeutic approach to orchestrate the regeneration and functional recovery of injured peripheral nerves.

A growing body of studies indicate that small noncoding RNAs, especially microRNAs (miRNA), play a crucial role in response to peripheral nerve injuries. During Wallerian degeneration and regeneration processes, they orchestrate several pathways, in particular the MAPK, AKT, and EGR2 (KROX20) pathways. Certain miRNAs show specific expression profiles upon a nerve lesion correlating with the subsequent nerve regeneration stages such as dedifferentiation and with migration of Schwann cells, uptake of debris, neurite outgrowth and finally remyelination of regenerated axons. This review highlights (a) the specific expression profiles of miRNAs upon a nerve lesion and (b) how miRNAs regulate nerve regeneration by acting on distinct pathways and linked proteins. Shedding light on the role of miRNAs associated with peripheral nerve regeneration will help researchers to better understand the molecular mechanisms and deliver targets for precision medicine.

Growth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve repair and regeneration. Our previous sequencing data showed that the mRNA coding for betacellulin (Btc), an epidermal growth factor protein family member, was up-regulated in rat sciatic nerve segment after nerve injury, implying the potential involvement of Btc during peripheral nerve regeneration.
Expression of Btc was examined in Schwann cells by immunostaining. The function of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or treating cells with Btc recombinant protein. The influence of Schwann cell-secreted Btc on neurons was determined using a co-culture assay. The in vivo effects of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated.
Immunostaining images and ELISA outcomes indicated that Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that transfection with siRNA against Btc impeded Schwann cell migration while application of exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells influenced neuron behavior and increased neurite length. In vivo evidence supported the promoting role of Btc in nerve regeneration after both rat sciatic nerve crush injury and transection injury.
Our findings demonstrate the essential roles of Btc on Schwann cell migration and axon elongation and imply the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.

Peripheral nerve injury (PNI) is common and, unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury. Peripheral myelinating glia, Schwann cells (SCs), interact with various cells in and around the injury site and are important for debris elimination, repair, and nerve regeneration. Following PNI, Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages. Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair. The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve. In particular, SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers. This mobility increases SC interactions with other cells in the nerve and the exogenous environment, which influence SC behavior post-injury. Following PNI, SCs directly and indirectly interact with other SCs, fibroblasts, and macrophages. In addition, the inter- and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve. This review provides a basic assessment of SC function post-PNI, as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and, ultimately, repair of the injured nerve.

Nerve regeneration after injury requires proper axon alignment to bridge the lesion site and myelination to achieve functional recovery. Transplanted scaffolds with aligned channels, have been shown to induce axon growth to some extent. However, the penetration of axons into the microchannels remain a challenge, influencing the functional recovery of regenerated nerves. We previously demonstrated that the size of microchannels exerts significant impact on Schwann cells (SCs) migration. Here we demonstrate that migration of SCs promotes, significantly, the dorsal root ganglion (DRG) neurons to extend axons into three-dimensional channels and form aligned fascicular-like axon tracts. Moreover, the migrating SCs attach and wrap around the aligned axons of DRG neurons in the microchannels and initiate myelination. The SCs release growth factors that provide chemotactic signals to the regenerating axons, similar to the response achieved with nerve growth factor (NGF), but with the additional capability of promoting myelination, thereby demonstrating the beneficial effects of including SCs over NGF alone in enhancing axon penetration and myelination in three-dimensional microchannels.

Synthetic nerve conduits have emerged as an alternative to guide axonal regeneration in peripheral nerve gap injuries. Migration of Schwann cells (SC) from nerve stumps has been demonstrated as one essential factor for nerve regeneration in nerve defects. In this experiment, SC viability and migration were investigated for various materials to determine the optimal conditions for nerve regeneration. Cell viability and SC migration assays were conducted for collagen I, laminin, fibronectin, lysine and ornithine. The highest values for cell viability were detected for collagen I, whereas fibronectin was most stimulatory for SC migration. At this time, clinically approved conduits are based on single-material structures. In contrast, the results of this experiment suggest that material compounds such as collagen I in conjunction with fibronectin should be considered for optimal nerve healing.

Alpinia oxyphylla MIQ (Alpinate Oxyphyllae Fructus, AOF) is an important traditional Chinese medicinal herb whose fruits is widely used to prepare tonics and is used as an aphrodisiac, anti salivary, anti diuretic and nerve-protective agent. Protocatechuic acid (PCA), a simple phenolic compound was isolated from the kernels of AOF. This study investigated the role of PCA in promoting neural regeneration and the underlying molecular mechanisms. Nerve regeneration is a complex physiological response that takes place after injury. Schwann cells play a crucial role in the endogenous repair of peripheral nerves due to their ability to proliferate and migrate. The role of PCA in Schwann cell migration was determined by assessing the induced migration potential of RSC96 Schwann cells. PCA induced changes in the expression of proteins of three MAPK pathways, as determined using Western blot analysis. In order to determine the roles of MAPK (ERK1/2, JNK, and p38) pathways in PCA-induced matrix-degrading proteolytic enzyme (PAs and MMP2/9) production, the expression of several MAPK-associated proteins was analyzed after siRNA-mediated inhibition assays. Treatment with PCA-induced ERK1/2, JNK, and p38 phosphorylation that activated the downstream expression of PAs and MMPs. PCA-stimulated ERK1/2, JNK and p38 phosphorylation was attenuated by individual pretreatment with siRNAs or MAPK inhibitors (U0126, SP600125, and SB203580), resulting in the inhibition of migration and the uPA-related signal pathway. Taken together, our data suggest that PCA extract regulate the MAPK (ERK1/2, JNK, and p38)/PA (uPA, tPA)/MMP (MMP2, MMP9) mediated regeneration and migration signaling pathways in Schwann cells. Therefore, PCA plays a major role in Schwann cell migration and the regeneration of damaged peripheral nerve.

Current injury models suggest that Schwann cell (SC) migration and guidance are necessary for successful regeneration and synaptic reconnection after peripheral nerve injury. The ability of conducting polymers such as polypyrrole (PPy) to exhibit chemical, contact and electrical stimuli for cells has led to much interest in their use for neural conduits. Despite this interest, there has been very little research on the effect that electrical stimulation (ES) using PPy has on SC behavior. Here we investigate the mechanism by which SCs interact with PPy in the presence of an electric field. Additionally, we explored the effect that the adsorption of different serum proteins on PPy upon the application of an electric field has on SC migration. The results indicate an increase in average displacement of the SC with ES, resulting in a net anodic migration. Moreover, indirect effects of protein adsorption due to the oxidation of the film upon the application of ES were shown to have a larger effect on migration speed than on migration directionality. These results suggest that SC migration speed is governed by an integrin- or receptor-mediated mechanism, whereas SC migration directionality is governed by electrically mediated phenomena. These data will prove invaluable in optimizing conducting polymers for their different biomedical applications such as nerve repair.

Erythropoietin-producing hepatocellular carcinoma receptors (Ephs) and their ligands Ephrins can affect axon growth. To evaluate the efficacy of EphA4 knockdown on Schwann cell migration and peripheral nerve regeneration, we detected EphA4 levels in Schwann cells. To knock down the expression of EphA4 in Schwann cell, two independent small interfering RNAs (siRNAs) were designed, and Schwann cell migration was examined. Four days after surgery, sciatic nerve sections of wild-type (WT) and EphA4(-/-) rats were examined by immunofluorescence, and axonal outgrowth was analyzed. The EphA4 protein could be detected in Schwann cells from intact nerves. EphA4 mediates the inhibitory effect on Schwann cell migration, and EphA4 knock-down can strongly increase Schwann cell migration and peripheral nerve regeneration. Knocking-down the expression of EphA4 promotes peripheral axon growth in vivo. It may provide a potential strategy for the recovery of peripheral nerve injury.