Chitosan/PLGA-based tissue engineered nerve grafts with SKP-SC-EVs enhance sciatic nerve regeneration in dogs through miR-30b-5p-mediated regulation of axon growth.

Extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs) promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats. This study aimed at expanding the application of SKP-SC-EVs in nerve grafting by creating a chitosan/PLGA-based, SKP-SC-EVs-containing tissue engineered nerve graft (TENG) to bridge a 40-mm long sciatic nerve defect in dogs. SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions, supported the outgrowth and myelination of regenerated axons, and alleviated the denervation-induced atrophy of target muscles in dogs. To clarify the underlying molecular mechanism, we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons, and miR-30b-5p was the most important among others. We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK, STAT3 or CREB. Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.

Skin derived precursors induced Schwann cells mediated tissue engineering-aided neuroregeneration across sciatic nerve defect.

A central question in neural tissue engineering is how the tissue-engineered nerve (TEN) translates detailed transcriptional signals associated with peripheral nerve regeneration into meaningful biological processes. Here, we report a skin-derived precursor-induced Schwann cell (SKP-SC)-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft (SKP-SCs-TEN) that can promote sciatic nerve regeneration and functional restoration nearly to the levels achieved by autologous nerve grafts according to behavioral, histological, and electrophysiological evidence. For achieving better effect of neuroregeneration, this is the first time to jointly apply a dynamic perfusion bioreactor and the ascorbic acid to stimulate the SKP-SCs secretion of extracellular matrix (ECM). To overcome the limitation of traditional tissue-engineered nerve grafts, jointly utilizing SKP-SCs and their ECM components were motivated by the thought of prolongating the effect of support cells and their bioactive cues that promote peripheral nerve regeneration. To further explore the regulatory model of gene expression and the related molecular mechanisms involved in tissue engineering-aided peripheral nerve regeneration, we performed a cDNA microarray analysis of gene expression profiling, a comprehensive bioinformatics analysis and a validation study on the grafted segments and dorsal root ganglia tissues. A wealth of transcriptomic and bioinformatics data has revealed complex molecular networks and orchestrated functional regulation that may be responsible for the effects of SKP-SCs-TEN on promoting peripheral nerve regeneration. Our work provides new insights into transcriptomic features and patterns of molecular regulation in nerve functional recovery aided by SKP-SCs-TEN that sheds light on the broader possibilities for novel repair strategies of peripheral nerve injury.

Corrigendum: Transcription factor SS18L1 regulates the proliferation, migration and differentiation of Schwann cells in peripheral nerve injury.

[This corrects the article DOI: 10.3389/fvets.2022.936620.].

A Hierarchically Nanofibrous Self-Cleaning Textile for Efficient Personal Thermal Management in Severe Hot and Cold Environments.

Climate change has recently caused more and more severe temperatures, inducing a growing demand for personal thermal management at outdoors. However, designing textiles that can achieve personal thermoregulation without energy consumption in severely hot and cold environments remains a huge challenge. Herein, a hierarchically nanofibrous (HNF) textile with improved thermal insulation and radiative thermal management functions is fabricated for efficient personal thermal management in severe temperatures. The textile consists of a radiative cooling layer, an intermediate thermal insulation layer, and a radiative heating layer, wherein the porous lignocellulose aerogel membrane (LCAM) as intermediate layer has low thermal conductivity (0.0366 W·m-1·K-1), ensuring less heat loss in cold weather and blocking external heat in hot weather. The introduction of polydimethylsiloxane (PDMS) increases the thermal emissivity (90.4%) of the radiative cooling layer in the atmospheric window and also endows it with a perfect self-cleaning performance. Solar absorptivity (80.1%) of the radiative heating layer is dramatically increased by adding only 0.05 wt% of carbon nanotubes (CNTs) into polyacrylonitrile. An outdoor test demonstrates that the HNF textile can achieve a temperature drop of 7.2 °C compared with white cotton in a hot environment and can be as high as 12.2 °C warmer than black cotton in a cold environment. In addition, the HNF textile possesses excellent moisture permeability, breathability, and directional perspiration performances, making it promising for personal thermal management in severely hot and cold environments.

Neural tissue-engineered prevascularization in vivo enhances peripheral neuroregeneration via rapid vascular inosculation.

Neural tissue engineering techniques typically face a significant challenge, simulating complex natural vascular systems that hinder the clinical application of tissue-engineered nerve grafts (TENGs). Here, we report a subcutaneously pre-vascularized TENG consisting of a vascular endothelial growth factor-induced host vascular network, chitosan nerve conduit, and inserted silk fibroin fibers. Contrast agent perfusion, tissue clearing, microCT scan, and blood vessel 3D reconstruction were carried out continuously to prove whether the regenerated blood vessels were functional. Moreover, histological and electrophysiological evaluations were also applied to investigate the efficacy of repairing peripheral nerve defects with pre-vascularized TENG. Rapid vascular inosculation of TENG pre-vascularized blood vessels with the host vascular system was observed at 4 â€‹d bridging the 10 â€‹mm sciatic nerve defect in rats. Transplantation of pre-vascularized TENG in vivo suppressed proliferation of vascular endothelial cells (VECs) while promoting their migration within 14 â€‹d post bridging surgery. More importantly, the early vascularization of TENG drives axonal regrowth by facilitating bidirectional migration of Schwann cells (SCs) and the bands of Büngner formation. This pre-vascularized TENG increased remyelination, promoted recovery of electrophysiological function, and prevented atrophy of the target muscles when observed 12 weeks post neural transplantation. The neural tissue-engineered pre-vascularization technique provides a potential approach to discover an individualized TENG and explore the innovative neural regenerative process.

Skin precursor-derived Schwann cells accelerate in vivo prevascularization of tissue-engineered nerves to promote peripheral nerve regeneration.

Prevascularization strategies have become a hot spot in tissue engineering. As one of the potential candidates for seed cells, skin precursor-derived Schwann cells (SKP-SCs) were endowed with a new role to more efficiently construct prevascularized tissue-engineered peripheral nerves. The silk fibroin scaffolds seeded with SKP-SCs were prevascularized through subcutaneously implantation, which was further assembled with the SKP-SC-containing chitosan conduit. SKP-SCs expressed pro-angiogenic factors in vitro and in vivo. SKP-SCs significantly accelerated the satisfied prevascularization in vivo of silk fibroin scaffolds compared with VEGF. Moreover, the NGF expression revealed that pregenerated blood vessels adapted to the nerve regeneration microenvironment through reeducation. The short-term nerve regeneration of SKP-SCs-prevascularization was obviously superior to that of non-prevascularization. At 12 weeks postinjury, both SKP-SCs-prevascularization and VEGF-prevascularization significantly improved nerve regeneration with a comparable degree. Our figures provide a new enlightenment for the optimization of prevascularization strategies and how to further utilize tissue engineering for better repair.

Pixel-Domain Just Noticeable Difference Modeling with Heterogeneous Color Features.

With the rapidly emerging user-generated images, perception compression for color image is an inevitable mission. Whilst in existing just noticeable difference (JND) models, color-oriented features are not fully taken into account for coinciding with HVS perception characteristics, such as sensitivity, attention, and masking. To fully imitate the color perception process, we extract color-related feature parameters as local features, including color edge intensity and color complexity, as well as region-wise features, including color area proportion, color distribution position and color distribution dispersion, and inherent feature irrelevant to color content called color perception difference. Then, the potential interaction among them is analyzed and modeled as color contrast intensity. To utilize them, color uncertainty and color saliency are envisaged to emanate from feature integration in the information communication framework. Finally, color and uncertainty saliency models are applied to improve the conventional JND model, taking the masking and attention effect into consideration. Subjective and objective experiments validate the effectiveness of the proposed model, delivering superior noise concealment capacity compared with start-of-the-art works.

Transcription factor SS18L1 regulates the proliferation, migration and differentiation of Schwann cells in peripheral nerve injury.

Transcription factors bind to specific DNA sequences, modulate the transcription of target genes, and regulate various biological processes, including peripheral nerve regeneration. Our previous analysis showed that SS18L1, a gene encoding the transcription factor SS18-like protein 1, was differentially expressed in the distal sciatic nerve stumps after rat sciatic nerve transection injury, but its effect on peripheral nerve injury has not been reported. In the current study, we isolated and cultured primary Schwann cells, and examined the role of SS18L1 for the biological functions of the cells. Depletion of SS18L1 by siRNA in Schwann cells enhanced cell proliferation and inhibited cell migration, as determined by EdU assay and transwell migration assay, respectively. In addition, silencing of SS18L1 inhibited Schwann cell differentiation induced by HRG and cAMP. Bioinformatics analyses revealed an interaction network of SS18L1, including DF2, SMARCD1, SMARCA4, and SMARCE1, which may be implicated in the regulatory functions of SS18L1 on the proliferation, migration and differentiation of Schwann cells. In conclusion, our results revealed a temporal expression profile of SS18L1 in peripheral nerve injury and its potential roles during the process of nerve recovery.

Blood vessel remodeling in late stage of vascular network reconstruction is essential for peripheral nerve regeneration.

One of the bottlenecks of advanced study on tissue engineering in regenerative medicine is rapid and functional vascularization. For a deeper comprehension of vascularization, the exhaustive, dynamic, and three-dimensional depiction of perfused vascular network reconstruction during peripheral nerve regeneration was performed using Micro-CT scanning. The 10 mm defect of sciatic nerve in rat was bridged by the autologous or tissue engineered nerve. The blood vessel anastomosis between nerve stumps and autologous nerve accomplished at 4 days to 1 week after surgery, which was a sufficient basis for the mature vascular network re-establishment. The stronger ability for sprouting angiogenesis and vascular remodeling of autologous nerve compared with tissue engineered nerve was revealed. However, common phases of vascularization in peripheral nerve regeneration were painted: hypoxic initiation, sprouting angiogenesis, and remodeling and maturation. The effect of less-concerned vascular remodeling on nerve regeneration was further analyzed after nerve crush injury. The blockage of vascular remodeling in late stage by VEGF injection significantly inhibited axons and myelin sheaths regeneration, which attenuated the impulse conduction toward reinnervated muscles. It was illustrated that a large amount of immature blood vessels rather than necessary vascular remodeling elevated local inflammation level in nerve regeneration microenvironment. The figures inspired us to understand the close connections between vascularization and peripheral nerve regeneration from a broader dimension to achieve better constructions, regulations and repair effects of tissue engineered nerves in clinic.

AMP-activated kinase regulates porcine reproductive and respiratory syndrome virus infection in vitro.

Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen in the pig industry worldwide. Many viruses manipulate their cellular metabolism to replicate themselves and cause infection. A conserved cellular energy sensor, 5'-AMP-activated protein kinase (AMPK), maintains cellular energy homeostasis. We found that PRRSV infection caused significant AMPK activation in a time-dependent manner via the ROS-calcium/calmodulin-dependent protein kinase-2 pathway. RNA interference-mediated AMPK knockdown could increase PRRSV replication in MARC-145 cells, suggesting that AMPK contributed to PRRSV infection regulation. Moreover, investigation of the effect of AMPK activity on PRRSV replication showed that PRRSV replication could be suppressed by the pharmacological agonists 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside and A769662. Conversely, an AMPK inhibitor, compound C, markedly enhanced PRRSV infection. Furthermore, the AMPK agonist A769662 was found to exert no effect on PRRSV entry, assembly, and release, suggesting that A769662 may hinder the PRRSV genome replication in MARC-145 cells. In conclusion, AMPK may be a promising antiviral drug target against PRRSV infection.

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.

The balanced microenvironment regulated by the degradants of appropriate PLGA scaffolds and chitosan conduit promotes peripheral nerve regeneration.

Tissue-engineered nerve grafts (TENGs) are the most promising way for repairing long-distance peripheral nerve defects. Chitosan and poly (lactic-co-glycolic acid) (PLGA) scaffolds are considered as the promising materials in the pharmaceutical and biomedical fields especially in the field of tissue engineering. To further clarify the effects of a chitosan conduit inserted with various quantity of poly (lactic-co-glycolic acid) (PLGA) scaffolds, and their degrades on the peripheral nerve regeneration, the chitosan nerve conduit inserted with different amounts of PLGA scaffolds were used to repair rat sciatic nerve defects. The peripheral nerve regeneration at the different time points was dynamically and comprehensively evaluated. Moreover, the influence of different amounts of PLGA scaffolds on the regeneration microenvironment including inflammatory response and cell state were also revealed. The modest abundance of PLGA is more instrumental to the success of nerve regeneration, which is demonstrated in terms of the structure of the regenerated nerve, reinnervation of the target muscle, nerve impulse conduction, and overall function. The PLGA scaffolds aid the migration and maturation of Schwann cells. Furthermore, the PLGA and chitosan degradation products in a correct ratio neutralize, reducing the inflammatory response and enhancing the regeneration microenvironment. The balanced microenvironment regulated by the degradants of appropriate PLGA scaffolds and chitosan conduit promotes peripheral nerve regeneration. The findings represent a further step towards programming TENGs construction, applying polyester materials in regenerative medicine, and understanding the neural regeneration microenvironment.

Protective effects and molecular mechanisms of Achyranthes bidentata polypeptide k on Schwann cells.

BACKGROUND: Achyranthes bidentata polypeptide k (ABPPk) is an active ingredient used in traditional Chinese medicine separated from Achyranthes bidentata polypeptides. So far, the role of ABPPk in peripheral nerve protection has not been comprehensively studied. METHODS: In this study, primary Schwann cells exposed to serum deprivation were treated with ABPPk or nerve growth factor (NGF) in vitro. Cell viability, cell apoptosis, apoptosis-related protein expression, and antioxidant enzyme activity were analyzed. To further explore the underlying molecular mechanisms and key regulatory molecules involved in the effects of ABPPk, integrative and dynamic bioinformatics analysis at different time points was carried out following RNA-seq of Schwann cells subjected to serum deprivation. RESULTS: We found that ABPPk could effectively reduce Schwann cell apoptosis caused by serum deprivation, which was comparable to NGF's anti-apoptotic effects. ABPPk had the largest number of upregulated and downregulated differential expression genes at the earliest 0.5 h time, while NGF had fewer differential expression genes at this early stage. The significant difference at this time point between the two groups was also displayed in heatmaps. The molecular regulation of diseases and functions and canonical pathways revealed that ABPPk had more participation and advantages in the vasculature and immune system areas, especially angiogenesis regulation. Also, ABPPk demonstrated an earlier start in these molecular regulations than NGF. Furthermore, the analysis of transcription factors also illustrated that ABPPk not only had more key initial regulatory factors participating in vascular-related processes, but these also remained for a longer period. There was no significant difference in neural-related molecular regulation between the two groups. CONCLUSIONS: Using high-throughput sequencing technology, our work unveiled the protective effects of ABPPk on Schwann cells after serum deprivation in a more comprehensive manner. These results further enrich the positive functions and molecular mechanisms of ABPPk and traditional Chinese medicine and benefit the discovery of novel therapeutic targets for peripheral nerve regeneration.

Hierarchical Predictive Coding-Based JND Estimation for Image Compression.

The human visual system (HVS) is a hierarchical system, in which visual signals are processed hierarchically. In this paper, the HVS is modeled as a three-level communication system and visual perception is divided into three stages according to the hierarchical predictive coding theory. Then, a novel just noticeable distortion (JND) estimation scheme is proposed. In visual perception, the input signals are predicted constantly and spontaneously in each hierarchy, and neural response is evoked by the central residue and inhibited by surrounding residues. These two types' residues are regarded as the positive and negative visual incentives which cause positive and negative perception effects, respectively. In neuroscience, the effect of incentive on observer is measured by the surprise of this incentive. Thus, we propose a surprise-based measurement method to measure both perception effects. Specifically, considering the biased competition of visual attention, we define the product of the residue self-information (i.e., surprise) and the competition biases as the perceptual surprise to measure the positive perception effect. As for the negative perception effect, it is measured by the average surprise (i.e., the local Shannon entropy). The JND threshold of each stage is estimated individually by considering both perception effects. The total JND threshold is finally obtained by non-linear superposition of three stage thresholds. Furthermore, the proposed JND estimation scheme is incorporated into the codec of Versatile Video Coding for image compression. Experimental results show that the proposed JND model outperforms the relevant existing ones, and over 16% of bit rate can be reduced without jeopardizing the perceptual quality.

Gene set enrichment analysis and protein-protein interaction network analysis after sciatic nerve injury.

BACKGROUND: Peripheral nerves are able to regenerate spontaneously after injury. An increasing number of studies have investigated the mechanism of peripheral nerve regeneration and attempted to find potential therapeutic targets. The various bioinformatics analysis tools available, gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) networks can effectively screen the crucial targets of neuroregeneration. METHODS: GSEA and PPI networks were constructed through ingenuity pathway analysis and sequential gene expression validation ex vitro to investigate the molecular processes at 1, 4, 7, and 14 days following sciatic nerve transection in rats. RESULTS: Immune response and the activation of related canonical pathways were classified as crucial biological events. Additionally, neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), neuregulin 1 (NRG1), nuclear factor of activated T cells 2 (NFATC2), midline 1 (MID1), GLI family zinc finger 2 (GLI2), and ventral anterior homeobox 1 (VAX1), which were jointly involved in both immune response and axonal regeneration, were screened and their mRNA and protein expressions following nerve injury were validated. Among them, the expression of VAX1 continuously increased following nerve injury, and it was considered to be a potential therapeutic target. CONCLUSIONS: The combined use of GSEA and PPI networks serves as a valuable way to identify potential therapeutic targets for neuroregeneration.

Construction of Dual-Biofunctionalized Chitosan/Collagen Scaffolds for Simultaneous Neovascularization and Nerve Regeneration.

Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration. However, most studies on novel biofunctionalized implants have emphasized the promotion of neuronal and axonal repair over vascularization, a process critical for long-term functional restoration. We constructed a dual-biofunctionalized chitosan/collagen composite scaffold with Ile-Lys-Val-Ala-Val (IKVAV) and vascular endothelial growth factor (VEGF) by combining solution blending, in situ lyophilization, and surface biomodification. Immobilization of VEGF and IKVAV on the scaffolds was confirmed both qualitatively by staining and quantitatively by ELISA. Various single- and dual-biofunctionalized scaffolds were compared for the promotion of endothelial cell (EC) and Schwann cell (SC) proliferation as well as the induction of angiogenic and neuroregeneration-associated genes by these cells in culture. The efficacy of these scaffolds for vascularization was evaluated by implantation in chicken embryos, while functional repair capacity in vivo was assessed in rats subjected to a 10 mm sciatic nerve injury. Dual-biofunctionalized scaffolds supported robust EC and SC proliferation and upregulated the expression levels of multiple genes and proteins related to neuroregeneration and vascularization. Dual-biofunctionalized scaffolds demonstrated superior vascularization induction in embryos and greater promotion of vascularization, myelination, and functional recovery in rats. These findings support the clinical potential of VEGF/IKVAV dual-biofunctionalized chitosan/collagen composite scaffolds for facilitating peripheral nerve regeneration, making it an attractive candidate for repairing critical nerve defect. The study may provide a critical experimental and theoretical basis for the development and design of new artificial nerve implants with excellent biological performance.

Ψ-Net: Focusing on the border areas of intracerebral hemorrhage on CT images.

BACKGROUND AND OBJECTIVE: The volume of the intracerebral hemorrhage (ICH) obtained from CT scans is essential for quantification and treatment planning. However,a fast and accurate volume acquisition brings great challenges. On the one hand, it is both time consuming and operator dependent for manual segmentation, which is the gold standard for volume estimation. On the other hand, low contrast to normal tissues, irregular shapes and distributions of the hemorrhage make the existing automatic segmentation methods hard to achieve satisfactory performance. METHOD: To solve above problems, a CNN-based architecture is proposed in this work, consisting of a novel model, which is named as Ψ-Net and a multi-level training strategy. In the structure of Ψ-Net, a self-attention block and a contextual-attention block is designed to suppresses the irrelevant information and segment border areas of the hemorrhage more finely. Further, an multi-level training strategy is put forward to facilitate the training process. By adding the slice-level learning and a weighted loss, the multi-level training strategy effectively alleviates the problems of vanishing gradient and the class imbalance. The proposed training strategy could be applied to most of the segmentation networks, especially for complex models and on small datasets. RESULTS: The proposed architecture is evaluated on a spontaneous ICH dataset and a traumatic ICH dataset. Compared to the previous works on the ICH sementation, the proposed architecture obtains the state-of-the-art performance(Dice of 0.950) on the spontaneous ICH, and comparable results(Dice of 0.895) with the best method on the traumatic ICH. On the other hand, the time consumption of the proposed architecture is much less than the previous methods on both training and inference. Morever, experiment results on various of models prove the universality of the multi-level training strategy. CONCLUSIONS: This study proposed a novel CNN-based architecture, Ψ-Net with multi-level training strategy. It takes less time for training and achives superior performance than previous ICH segmentaion methods.

Sequencing analysis of matrix metalloproteinase 7-induced genetic changes in Schwann cells.

Previous research revealed the positive activity of matrix metalloproteinase 7 (MMP7) on migration and myelin regeneration of Schwann cells (SCs). However, understanding of the molecular changes and biological activities induced by increased amounts of MMP7 in SCs remains limited. To better understand the underlying molecular events, primary SCs were isolated from the sciatic nerve stump of newborn rats and cultured with 10 nM human MMP7 for 24 hours. The results of genetic testing were analyzed at a relatively relaxed threshold value (fold change ≥ 1.5 and P-value < 0.05). Upon MMP7 exposure, 149 genes were found to be upregulated in SCs, whereas 133 genes were downregulated. Gene Ontology analysis suggested that many differentially expressed molecules were related to cellular processes, single-organism processes, and metabolic processes. Kyoto Enrichment of Genes and Genomes pathway analysis further indicated the critical involvement of cell signaling and metabolism in MMP7-induced molecular regulation of SCs. Results of Ingenuity Pathway Analysis (IPA) also revealed that MMP7 regulates biological processes, molecular functions, cellular components, diseases and functions, biosynthesis, material metabolism, cell movement, and axon guidance. The outcomes of further analysis will deepen our comprehension of MMP7-induced biological changes in SCs. This study was approved by the Laboratory Animal Ethics Committee of Nantong University, China (approval No. 20190225-004) on February 27, 2019.

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.

Tau modulates Schwann cell proliferation, migration and differentiation following peripheral nerve injury.

Tau protein (encoded by the gene microtubule-associated protein tau, Mapt) is essential for the assembly and stability of microtubule and the functional maintenance of the nervous system. Tau is highly abundant in neurons and is detectable in astrocytes and oligodendrocytes. However, whether tau is present in Schwann cells, the unique glial cells in the peripheral nervous system, is unclear. Here, we investigated the presence of tau and its coding mRNA, Mapt, in cultured Schwann cells and find that tau is present in these cells. Gene silencing of Mapt promoted Schwann cell proliferation and inhibited Schwann cell migration and differentiation. In vivo application of Mapt siRNA suppressed the migration of Schwann cells after sciatic nerve injury. Consistent with this, Mapt-knockout mice showed elevated proliferation and reduced migration of Schwann cells. Rats injected with Mapt siRNA and Mapt-knockout mice also exhibited impaired myelin and lipid debris clearance. The expression and distribution of the cytoskeleton proteins α-tubulin and F-actin were also disrupted in these animals. These findings demonstrate the existence and biological effects of tau in Schwann cells, and expand our understanding of the function of tau in the nervous system.