scholarly journals BMP-7/Smad expression in dedifferentiated Schwann cells during axonal regeneration and upregulation of endogenous BMP-7 following administration of PTH (1-34)

2018 ◽  
Vol 26 (3) ◽  
pp. 230949901881295 ◽  
Author(s):  
Naoki Kokubu ◽  
Masaya Tsujii ◽  
Koji Akeda ◽  
Takahiro Iino ◽  
Akihiro Sudo
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Axonal Regeneration ◽  
Double Immunostaining ◽  
Aneurysm Clip ◽  
Smad Signaling ◽  
Bmp Receptors ◽  
Smad Protein

Purpose: To determine the expression and distribution of bone morphogenetic protein (BMP)-7 and related molecules during peripheral nerve regeneration and to assess whether administration of parathyroid hormone (PTH) drug (1-34) potentiates the intrinsic upregulation of BMP-7/Smad signaling. Methods: The rat sciatic nerves were crushed with an aneurysm clip resulting in axonal degeneration. In the normal nerve, and at 1, 2, 4, and 8 weeks after injury, BMP-7, BMP receptors, p-Smad 1/5/8, and Noggin, the endogenous BMP antagonist, were evaluated. Additionally, the distribution of BMP-7 was assessed by fluorescent double immunostaining. In vitro studies were also performed to examine the effect of BMP-7 and PTH (1-34) administration on rat Schwann cells (SCs). Results: Aneurysm clip made reliable animal model of the nerve injury with recovery at 8 weeks after the injury. BMP-7/Smad protein and mRNA were significantly upregulated on axon-SCs units at 1 week after injury, and this upregulated expression was maintained for 4 weeks. Besides, significant upregulation of Noggin’s expression was observed on axon-SCs units at 2 weeks after injury. Moreover, fluorescent double immunostaining showed co-localization between expression of BMP-7 and p75NTR during axonal regeneration. In the in vitro study, administration of BMP-7 induced significant proliferation of SCs. Application of PTH (1-34) upregulated BMP-7 on SCs. Discussion/conclusion: BMPs were reported to be involved in protection and recovery after injury as well as in neurogenesis. Our current study showed that BMP/Smad signaling molecules were upregulated on dedifferentiated SCs after peripheral nerve injury and that administration of BMP-7 increased SC viability in vitro. These results suggested that axonal regeneration could be induced via upregulation of endogenous BMP-7 on SCs by PTH (1-34) administration.

scholarly journals Ferulic Acid Enhances Peripheral Nerve Regeneration across Long Gaps

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Sheng-Chi Lee ◽  
Chin-Chuan Tsai ◽  
Chun-Hsu Yao ◽  
Yueh-Sheng Chen ◽  
Ming-Chang Wu
Keyword(s):  
Peripheral Nerve ◽  
Ferulic Acid ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Treated Group ◽  
Saline Control ◽  
Control Group ◽  
Rubber Tube

This study investigated the effect of ferulic acid (FA) on peripheral nerve injury. In thein vitrotest, the effect of FA on viability of Schwann cells was studied. In thein vivotest, right sciatic nerves of the rats were transected, and a 15 mm nerve defect was created. A nerve conduit made of silicone rubber tube filled with FA (5 and 25 μg/mL), or saline (control), was implanted into the nerve defect. Results show that the number of proliferating Schwann cells increased significantly in the FA-treated group at 25 μg/mL compared to that in the control group. After 8 weeks, the FA-treated group at 25 μg/mL had a higher rate of successful regeneration across the wide gap, a significantly calcitonin gene-related peptide (CGRP) staining of the lamina I-II regions in the dorsal horn ipsilateral to the injury, a significantly diminished number of macrophages recruited, and a significantly shortening of the latency and an acceleration of the nerve conductive velocity (NCV) of the evoked muscle action potentials (MAPs) compared with the controls. In summary, the FA may be useful in the development of future strategies for the treatment of peripheral nerve injury.

scholarly journals Salidroside promotes peripheral nerve regeneration based on tissue engineering strategy using Schwann cells and PLGA: in vitro and in vivo

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Hui Liu ◽  
Peizhen Lv ◽  
Yongjia Zhu ◽  
Huayu Wu ◽  
Kun Zhang ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerve Regeneration ◽  
Immunohistochemical Analysis ◽  
Neuroprotective Effects

Abstract Salidriside (SDS), a phenylpropanoid glycoside derived from Rhodiola rosea L, has been shown to be neuroprotective in many studies, which may be promising in nerve recovery. In this study, the neuroprotective effects of SDS on engineered nerve constructed by Schwann cells (SCs) and Poly (lactic-co-glycolic acid) (PLGA) were studied in vitro. We further investigated the effect of combinational therapy of SDS and PLGA/SCs based tissue engineering on peripheral nerve regeneration based on the rat model of nerve injury by sciatic transection. The results showed that SDS dramatically enhanced the proliferation and function of SCs. The underlying mechanism may be that SDS affects SCs growth through the modulation of neurotrophic factors (BDNF, GDNF and CNTF). 12 weeks after implantation with a 12 mm gap of sciatic nerve injury, SDS-PLGA/SCs achieved satisfying outcomes of nerve regeneration, as evidenced by morphological and functional improvements upon therapy by SDS, PLGA/SCs or direct suture group assessed by sciatic function index, nerve conduction assay, HE staining and immunohistochemical analysis. Our results demonstrated the significant role of introducing SDS into neural tissue engineering to promote nerve regeneration.

scholarly journals Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jiawei Xu ◽  
Jinkun Wen ◽  
Lanya Fu ◽  
Liqiang Liao ◽  
Ying Zou ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Axonal Regeneration ◽  
Wallerian Degeneration ◽  
Future Application ◽  
Injured Nerve

Abstract Background Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury. Methods Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the LyzCre+/−; RhoAflox/flox (cKO) mice or Lyz2Cre+/− (Cre) mice, regardless of sex. Macrophages’ migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages. Results 1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages. Conclusions Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.

scholarly journals Upregulated lncARAT in Schwann cells promotes axonal regeneration through recruiting macrophages and inducing macrophages M2 polarization

2021 ◽  
Author(s):  
Gang Yin ◽  
Yaofa Lin ◽  
Peilin Wang ◽  
Jun Zhou ◽  
Haodong Lin
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Noncoding Rna ◽  
Macrophage Polarization ◽  
Nerve Repair ◽  
M2 Polarization ◽  
Sciatic Nerves

Abstract BackgroundAxonal regeneration following peripheral nerve injury largely depends on a favorable microenvironment. Schwann cells (SCs) play a crucial role in axonal regeneration by interacting with macrophages, but the mechanisms underlying macrophages recruitment and polarization remain unclear.MethodsThe total RNA of crushed sciatic nerves and intact contralateral nerves was extracted and used to RNA-sequencing (RNA-seq). The differentially expressed long noncoding RNA (lncRNA) and mRNAs were analyzed using bioinformatics analysis, and were verified using qPCR and western blot analysis. The putative role of lncRNA in nerve regeneration was analyzed in vitro and in vivo. Macrophage polarization phenotype was identified by assessing IL-10, Arg-1, and CD206.ResultsHere we identified an lncRNA, termed Axon Regeneration-Associated Transcript (lncARAT), upregulated in SCs and SCs-derived exosomes after crushed sciatic nerves (CSN). LncARAT contributed to axonal regeneration and improved motor functional recovery. Mechanistically, lncARAT epigenetically activated CCL2 expression by recruiting KMT2A to CCL2 promoter, which resulted in an increased H3K4 trimethylation and CCL2 transcription in SCs. CCL2 upregulation facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. Once in macrophage, lncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p, resulting in an increased SOCS2 expression, which facilitated macrophage M2 polarization through a STAT1/6-dependent pathway, thus promoted axonal regeneration.ConclusionsLncARAT may serve as a promising therapeutic avenue for peripheral nerve repair.

scholarly journals Perspective on Schwann Cells Derived from Induced Pluripotent Stem Cells in Peripheral Nerve Tissue Engineering

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2497
Author(s):  
Zhong Huang ◽  
Rebecca Powell ◽  
James B. Phillips ◽  
Kirsten Haastert-Talini
Keyword(s):  
Stem Cells ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Induced Pluripotent Stem Cells ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Pluripotent Stem Cells ◽  
Peripheral Nerve Injury ◽  
Induced Pluripotent

Schwann cells play a crucial role in successful peripheral nerve repair and regeneration by supporting both axonal growth and myelination. Schwann cells are therefore a feasible option for cell therapy treatment of peripheral nerve injury. However, sourcing human Schwann cells at quantities required for development beyond research is challenging. Due to their availability, rapid in vitro expansion, survival, and integration within the host tissue, stem cells have attracted considerable attention as candidate cell therapies. Among them, induced pluripotent stem cells (iPSCs) with the associated prospects for personalized treatment are a promising therapy to take the leap from bench to bedside. In this critical review, we firstly focus on the current knowledge of the Schwann cell phenotype in regard to peripheral nerve injury, including crosstalk with the immune system during peripheral nerve regeneration. Then, we review iPSC to Schwann cell derivation protocols and the results from recent in vitro and in vivo studies. We finally conclude with some prospects for the use of iPSCs in clinical settings.

scholarly journals Upregulated lncARAT in Schwann Cells Promotes Axonal Regeneration through Recruiting Macrophages and Inducing Macrophages M2 Polarization

2021 ◽  
Author(s):  
Gang Yin ◽  
Yaofa Lin ◽  
Peilin Wang ◽  
Jun Zhou ◽  
Haodong Lin
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Noncoding Rna ◽  
Macrophage Polarization ◽  
Nerve Repair ◽  
M2 Polarization ◽  
Sciatic Nerves

Abstract Background: Axonal regeneration following peripheral nerve injury largely depends on a favorable microenvironment. Schwann cells (SCs) play a crucial role in axonal regeneration by interacting with macrophages, but the mechanisms underlying macrophages recruitment and polarization remain unclear. Methods: The total RNA of crushed sciatic nerves and intact contralateral nerves was extracted and used to RNA-sequencing (RNA-seq). The differentially expressed long noncoding RNA (lncRNA) and mRNAs were analyzed using bioinformatics analysis, and were verified using qPCR and western blot analysis. The putative role of lncRNA in nerve regeneration was analyzed in vitro and in vivo. Macrophage polarization phenotype was identified by assessing IL-10, Arg-1, and CD206.Results: Here we identified an lncRNA, termed Axon Regeneration-Associated Transcript (lncARAT), upregulated in SCs and SCs-derived exosomes after crushed sciatic nerves (CSN). LncARAT contributed to axonal regeneration and improved motor functional recovery. Mechanistically, lncARAT epigenetically activated CCL2 expression by recruiting KMT2A to CCL2 promoter, which resulted in an increased H3K4 trimethylation and CCL2 transcription in SCs. CCL2 upregulation facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. Once in macrophage, lncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p, resulting in an increased SOCS2 expression, which facilitated macrophage M2 polarization through a STAT1/6-dependent pathway, thus promoted axonal regeneration. Conclusions: LncARAT may serve as a promising therapeutic avenue for peripheral nerve repair.

scholarly journals Pleiotrophin Cellular Localization in Nerve Regeneration after Peripheral Nerve Injury

2005 ◽  
Vol 53 (8) ◽  
pp. 971-977 ◽  
Author(s):  
Brigitte Blondet ◽  
Gilles Carpentier ◽  
Fouad Lafdil ◽  
Jose Courty
Keyword(s):  
Endothelial Cells ◽  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Cellular Localization ◽  
Heparin Binding

Pleiotrophin (PTN) is a member of the family of heparin-binding growth factors that displays mitogenic activities and promotes neurite outgrowth in vitro. In vivo, PTN is widely expressed along pathways of developing axons during the late embryonic and early postnatal period. Although the level of PTN gene expression is very low during adulthood, activation of the gene may occur during recovery from injury and seems to play an important role in tissue regeneration processes. In this study, we investigated whether PTN was involved in the regenerative process of injured peripheral nerves. To refer localization of the fluorescent markers to myelinated axons, we developed a specific computer tool for colocalization of fluorescence images with phase contrast images. Immunohistochemical analysis showed PTN in different types of nonneural cells in distal nerve segments, including Schwann cells, macrophages, and endothelial cells, but not in axons. Schwann cells exhibited PTN immunoreactivity as early as 2 days after injury, whereas PTN-positive macrophages were found 1 week later. Strong PTN immunoreactivity was noted in endothelial cells at all time points. These findings support the idea that PTN participates in the adaptive response to peripheral nerve injury. A better understanding of its contribution may suggest new strategies for enhancing peripheral nerve regeneration.

scholarly journals The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
John A. Fissel ◽  
Mohamed H. Farah
Keyword(s):  
Peripheral Nerve ◽  
Cell Signaling ◽  
Nerve Regeneration ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Axonal Regeneration ◽  
Current Knowledge ◽  
Peripheral Nerve Regeneration ◽  
Immunomodulatory Activity ◽  
Macrophage Recruitment

AbstractFollowing peripheral nerve injury, multiple cell types, including axons, Schwann cells, and macrophages, coordinate to promote nerve regeneration. However, this capacity for repair is limited, particularly in older populations, and current treatments are insufficient. A critical component of the regeneration response is the network of cell-to-cell signaling in the injured nerve microenvironment. Sheddases are expressed in the peripheral nerve and play a role in the regulation if this cell-to-cell signaling through cleavage of transmembrane proteins, enabling the regulation of multiple pathways through cis- and trans-cellular regulatory mechanisms. Enhanced axonal regeneration has been observed in mice with deletion of the sheddase beta-secretase (BACE1), a transmembrane aspartyl protease that has been studied in the context of Alzheimer’s disease. BACE1 knockout (KO) mice display enhanced macrophage recruitment and activity following nerve injury, although it is unclear whether this plays a role in driving the enhanced axonal regeneration. Further, it is unknown by what mechanism(s) BACE1 increases macrophage recruitment and activity. BACE1 has many substrates, several of which are known to have immunomodulatory activity. This review will discuss current knowledge of the role of BACE1 and other sheddases in peripheral nerve regeneration and outline known immunomodulatory BACE1 substrates and what potential roles they could play in peripheral nerve regeneration. Currently, the literature suggests that BACE1 and substrates that are expressed by neurons and Schwann cells are likely to be more important for this process than those expressed by macrophages. More broadly, BACE1 may play a role as an effector of immunomodulation beyond the peripheral nerve.

scholarly journals Interleukin-4 Regulates the Expression of CD209 and Subsequent Uptake of Mycobacterium leprae by Schwann Cells in Human Leprosy

2010 ◽  
Vol 78 (11) ◽  
pp. 4634-4643 ◽  
Author(s):  
Rosane M. B. Teles ◽  
Stephan R. Krutzik ◽  
Maria T. Ochoa ◽  
Rosane B. Oliveira ◽  
Euzenir N. Sarno ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Primary Cultures ◽  
Mycobacterium Leprae ◽  
Microbial Pathogens ◽  
Interleukin 4 ◽  
Common Mechanism ◽  
Specific Cell

ABSTRACT The ability of microbial pathogens to target specific cell types is a key aspect of the pathogenesis of infectious disease. Mycobacterium leprae, by infecting Schwann cells, contributes to nerve injury in patients with leprosy. Here, we investigated mechanisms of host-pathogen interaction in the peripheral nerve lesions of leprosy. We found that the expression of the C-type lectin, CD209, known to be expressed on tissue macrophages and to mediate the uptake of M. leprae, was present on Schwann cells, colocalizing with the Schwann cell marker, CNPase (2′,3′-cyclic nucleotide 3′-phosphodiesterase), along with the M. leprae antigen PGL-1 in the peripheral nerve biopsy specimens. In vitro, human CD209-positive Schwann cells, both from primary cultures and a long-term line, have a higher binding of M. leprae compared to CD209-negative Schwann cells. Interleukin-4, known to be expressed in skin lesions from multibacillary patients, increased CD209 expression on human Schwann cells and subsequent Schwann cell binding to M. leprae, whereas Th1 cytokines did not induce CD209 expression on these cells. Therefore, the regulated expression of CD209 represents a common mechanism by which Schwann cells and macrophages bind and take up M. leprae, contributing to the pathogenesis of leprosy.

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