Peripheral nerve regeneration by transplantation of bone marrow stromal cell—derived Schwann cells in adult rats

Object. Bone marrow stromal cells (BMSCs) can be induced to form Schwann cells by sequentially treating the cells with β-mercaptoethanol and retinoic acid, followed by forskolin and neurotrophic factors including heregulin. In this study the authors made artificial grafts filled with BMSC-derived Schwann cells (BMSC-DSCs) and transplanted them into the transected sciatic nerve in adult rats to evaluate the potential of BMSCs as a novel alternative method of peripheral nerve regeneration. Methods. The BMSC-DSCs were suspended in Matrigel and transferred into hollow fibers (12 mm in length), which were transplanted into the transected sciatic nerve in adult Wistar rats. Six months after cell transplantation, electrophysiological evaluation and walking track analysis were performed. Results of these studies showed significant improvement in motor nerve conduction velocity and sciatic nerve functional index in the BMSC-DSC—transplanted group compared with the control group (Matrigel graft only). Immunohistochemical study data demonstrated that transplanted BMSCs labeled with retrovirus green fluorescent protein were positive for P0 and myelin-associated glycoprotein and had reconstructed nodes of Ranvier and remyelinated regenerated nerve axons. The number of regenerated axons in the axial section of the central portion of the graft was significantly greater in the transplanted group. Although BMSCs can differentiate into several types of cells, tumor formation did not occur 6 months after engraftment. Conclusions. Results in this study indicate that BMSC-DSCs have great potential to promote regeneration of peripheral nerves. The artificial graft made with BMSC-DSCs represents an alternative method for the difficult reconstruction of a long distance gap in a peripheral nerve.

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IL-17F depletion accelerates chitosan conduit guided peripheral nerve regeneration

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01227-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Feixiang Chen ◽

Weihuang Liu ◽

Qiang Zhang ◽

Ping Wu ◽

Ao Xiao ◽

...

Keyword(s):

Bone Marrow ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Knockout Mice ◽

Inflammatory Markers ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Wild Type ◽

Anti Inflammatory

AbstractPeripheral nerve injury is a serious health problem and repairing long nerve deficits remains a clinical challenge nowadays. Nerve guidance conduit (NGC) serves as the most promising alternative therapy strategy to autografts but its repairing efficiency needs improvement. In this study, we investigated whether modulating the immune microenvironment by Interleukin-17F (IL-17F) could promote NGC mediated peripheral nerve repair. Chitosan conduits were used to bridge sciatic nerve defect in IL-17F knockout mice and wild-type mice with autografts as controls. Our data revealed that IL-17F knockout mice had improved functional recovery and axonal regeneration of sciatic nerve bridged by chitosan conduits comparing to the wild-type mice. Notably, IL-17F knockout mice had enhanced anti-inflammatory macrophages in the NGC repairing microenvironment. In vitro data revealed that IL-17F knockout peritoneal and bone marrow derived macrophages had increased anti-inflammatory markers after treatment with the extracts from chitosan conduits, while higher pro-inflammatory markers were detected in the Raw264.7 macrophage cell line, wild-type peritoneal and bone marrow derived macrophages after the same treatment. The biased anti-inflammatory phenotype of macrophages by IL-17F knockout probably contributed to the improved chitosan conduit guided sciatic nerve regeneration. Additionally, IL-17F could enhance pro-inflammatory factors production in Raw264.7 cells and wild-type peritoneal macrophages. Altogether, IL-17F may partially mediate chitosan conduit induced pro-inflammatory polarization of macrophages during nerve repair. These results not only revealed a role of IL-17F in macrophage function, but also provided a unique and promising target, IL-17F, to modulate the microenvironment and enhance the peripheral nerve regeneration.

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Histopathological analysis of gangliosides use in peripheral nerve regeneration after axonotmesis in rats

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502008000400011 ◽

2008 ◽

Vol 23 (4) ◽

pp. 364-371 ◽

Cited By ~ 3

Author(s):

Camila Maria Beder Ribeiro ◽

Belmiro Cavalcanti do Egito Vasconcelos ◽

Joaquim Celestino da Silva Neto ◽

Valdemiro Amaro da Silva Júnior ◽

Nancy Gurgel Figueiredo

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Peripheral Nerve Regeneration ◽

Cell Activity ◽

Control Group ◽

Histopathological Analysis ◽

Male Wistar Rats ◽

The Right

PURPOSE: To analyze the action of gangliosides in peripheral nerve regeneration in the sciatic nerve of the rat. METHODS: The sample was composed of 96 male Wistar rats. The animals were anaesthetized and, after identification of the anaesthesic plane, an incision was made in the posterior region of the thigh, followed by skin and muscle divulsion. The right sciatic nerve was isolated and compressed for 2 minutes. Continuous suture of the skin was performed. The animals were randomly divided into two groups: the experimental group (EG), which received subcutaneous injection of gangliosides, and the control group (CG), which received saline solution (0.9%) to mimic the effects of drug administration. RESULTS: No differences were observed between the experimental and control groups evaluated on the eighth day of observation. At 15 and 30 days the EG showed an decrease in Schwann cell activity and an apparent improvement in fibre organization; at 60 days, there was a slight presence of Schwann cells in the endoneural space and the fibres were organized, indicating nerve regeneration. At 15 and 30 days, the level of cell reaction in the CG had diminished, but there were many cells with cytoplasm in activity and in mitosis; at 60 days, hyperplastic Schwann cells and mitotic activity were again observed, as well as nerve regeneration, but to a lesser extent than in the EG. CONCLUSION: The administration of exogenous gangliosides seems to improve nerve regeneration.

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Effects of human amniotic fluid on peripheral nerve scarring and regeneration in rats

Journal of Neurosurgery ◽

10.3171/jns.2003.98.2.0371 ◽

2003 ◽

Vol 98 (2) ◽

pp. 371-377 ◽

Cited By ~ 41

Author(s):

Güzin Yeşim Özgenel ◽

Gülaydan Filiz

Keyword(s):

Peripheral Nerve ◽

Amniotic Fluid ◽

Nerve Regeneration ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Control Group ◽

Human Amniotic Fluid ◽

Content Type ◽

Repair Site ◽

Fine Print

Object. Peripheral nerve repair surgery is still replete with challenges. Despite technical improvements in microsurgery, classic methods of nerve repair have failed to provide satisfactory results. The purpose of this study was to investigate the effects of amniotic fluid from humans on peripheral nerve scarring and regeneration in rats. Methods. Forty adult Sprague—Dawley rats were used in this study. After the right sciatic nerve in each rat was transected and repaired using an epineural suture procedure, the nerves were divided into two groups according to the solution applied around the repair site: experimental group, 0.3 ml human amniotic fluid (HAF); and control group, 0.3 ml saline. Macroscopic and histological evaluations of peripheral nerve scarring were performed 4 weeks postsurgery. Nerves treated with HAF demonstrated a significant reduction in the amount of scar tissue surrounding the repair site (p < 0.05). No evidence of a reaction against HAF was noted. Functional nerve regeneration was measured once every 2 weeks by using a sciatic function index until 12 weeks postsurgery. Functional recovery in nerves treated with amniotic fluid occurred significantly faster than that in nerves treated with saline (p < 0.05). Peripheral nerve regeneration was evaluated histomorphologically at 12 weeks postsurgery. Nerves treated with amniotic fluid showed significant improvement with respect to the indices of fiber maturation (p < 0.05). Conclusions. Preliminary data show that HAF enhances peripheral nerve regeneration. The preventive effect of HAF on epineural scarring and the rich content of neurotrophic and neurite-promoting factors possibly contribute to this result.

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Nogo-C Inhibits Peripheral Nerve Regeneration by Regulating Schwann Cell Apoptosis and Dedifferentiation

Frontiers in Neuroscience ◽

10.3389/fnins.2020.616258 ◽

2021 ◽

Vol 14 ◽

Author(s):

Bo Jia ◽

Wei Huang ◽

Yu Wang ◽

Peng Zhang ◽

Zhiwei Wang ◽

...

Keyword(s):

Sciatic Nerve ◽

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Nerve Injury ◽

Cell Apoptosis ◽

Peripheral Nerve Regeneration ◽

Nerve Fibers ◽

Cell Dedifferentiation

While Nogo protein demonstrably inhibits nerve regeneration in the central nervous system (CNS), its effect on Schwann cells in peripheral nerve repair and regeneration following sciatic nerve injury remains unknown. In this research, We assessed the post-injury expression of Nogo-C in an experimental mouse model of sciatic nerve-crush injury. Nogo-C knockout (Nogo-C–/–) mouse was generated to observe the effect of Nogo-C on sciatic nerve regeneration, Schwann cell apoptosis, and myelin disintegration after nerve injury, and the effects of Nogo-C on apoptosis and dedifferentiation of Schwann cells were observed in vitro. We found that the expression of Nogo-C protein at the distal end of the injured sciatic nerve increased in wild type (WT) mice. Compared with the injured WT mice, the proportion of neuronal apoptosis was significantly diminished and the myelin clearance rate was significantly elevated in injured Nogo-C–/– mice; the number of nerve fibers regenerated and the degree of myelination were significantly elevated in Nogo-C–/– mice on Day 14 after injury. In addition, the recovery of motor function was significantly accelerated in the injured Nogo-C–/– mice. The overexpression of Nogo-C in primary Schwann cells using adenovirus-mediated gene transfer promoted Schwann cells apoptosis. Nogo-C significantly reduced the ratio of c-Jun/krox-20 expression, indicating its inhibition of Schwann cell dedifferentiation. Above all, we hold the view that the expression of Nogo-C increases following peripheral nerve injury to promote Schwann cell apoptosis and inhibit Schwann cell dedifferentiation, thereby inhibiting peripheral nerve regeneration.

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The effect of exercise on mobilization of hematopoietic progenitor cells involved in the repair of sciatic nerve crush injury [RETRACTED]

Journal of Neurosurgery ◽

10.3171/2012.8.jns111580 ◽

2013 ◽

Vol 118 (3) ◽

pp. 594-605 ◽

Cited By ~ 6

Author(s):

Fu-Chou Cheng ◽

Meei-Ling Sheu ◽

Hong-Lin Su ◽

Ying-Ju Chen ◽

Chun-Jung Chen ◽

...

Keyword(s):

Bone Marrow ◽

Sciatic Nerve ◽

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Progenitor Cells ◽

Treadmill Exercise ◽

Peripheral Nerve Regeneration ◽

Hematopoietic Progenitor Cells ◽

Hematopoietic Progenitor

Object Mobilization of hematopoietic progenitor cells (HPCs) from bone marrow involved in the process of peripheral nerve regeneration occurs mostly through deposits of CD34+ cells. Treadmill exercise, with either differing intensity or duration, has been shown to increase axon regeneration and sprouting, but the effect of mobilization of HPCs on peripheral nerve regeneration due to treadmill exercise has not yet been elucidated. Methods Peripheral nerve injury was induced in Sprague-Dawley rats by crushing the left sciatic nerve using a vessel clamp. The animals were categorized into 2 groups: those with and without treadmill exercise (20 m/min for 60 minutes per day for 7 days). Cytospin and flow cytometry were used to determine bone marrow progenitor cell density and distribution. Neurobehavioral analysis, electrophysiological study, and regeneration marker expression were investigated at 1 and 3 weeks after exercise. The accumulation of HPCs, immune cells, and angiogenesis factors in injured nerves was determined. A separate chimeric mice study was conducted to assess CD34+ cell distribution according to treadmill exercise group. Results Treadmill exercise significantly promoted nerve regeneration. Increased Schwann cell proliferation, increased neurofilament expression, and decreased Schwann cell apoptosis were observed 7 days after treadmill exercise. Elevated expression of S100 and Luxol fast blue, as well as decreased numbers of vacuoles, were identified in the crushed nerve 3 weeks after treadmill exercise. Significantly increased numbers of mononuclear cells, particularly CD34+ cells, were induced in bone marrow after treadmill exercise. The deposition of CD34+ cells was abolished by bone marrow irradiation. In addition, deposits of CD34+ cells in crushed nerves paralleled the elevated expressions of von Willebrand factor, isolectin B4, and vascular endothelial growth factor. Conclusions Bone marrow HPCs, especially CD34+ cells, were able to be mobilized by low-intensity treadmill exercise, and this effect paralleled the significant expression of angiogenesis factors. Treadmill exercise stimulation of HPC mobilization during peripheral nerve regeneration could be used as a therapy in human beings.

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Regeneration of rat sciatic nerve across a LactoSorb bioresorbable conduit with interposed short-segment nerve grafts

Journal of Neurosurgery ◽

10.3171/jns.2003.99.3.0549 ◽

2003 ◽

Vol 99 (3) ◽

pp. 549-554 ◽

Cited By ~ 29

Author(s):

Paul C. Francel ◽

Kevin S. Smith ◽

F. Alan Stevens ◽

Soon C. Kim ◽

James Gossett ◽

...

Keyword(s):

Sciatic Nerve ◽

Nerve Regeneration ◽

Peripheral Nerve Regeneration ◽

Sprague Dawley ◽

Silicone Tube ◽

Group V ◽

Content Type ◽

Nerve Segment ◽

Group I ◽

Fine Print

Object. This study was conducted to evaluate peripheral nerve regeneration through a conduit composed of a bioresorbable material (LactoSorb). Methods. Sprague—Dawley rats weighing approximately 250 g were randomized into five groups. A 20-mm-long sciatic nerve gap was created, then it was bridged by a reverse nerve autograft (Group I), an empty silicone tube (Group II), a silicone tube containing a short (2-mm) interposed nerve segment (Group III), an empty LactoSorb conduit (Group IV), or a LactoSorb conduit containing a 2-mm interposed nerve segment (Group V). The intact sciatic nerve served as the control in each animal. At 16 weeks postoperatively, no nerve regeneration was observed through either the empty silicone tube or the empty LactoSorb conduit. There was regeneration in all animals receiving the reverse autograft as well as in all animals receiving the silicone or LactoSorb conduit containing the 2-mm interposed nerve segment. Effective regeneration was assessed based on histological, electrophysiological, and morphometric criteria. Conclusions. The results indicate that a conduit made of resorbable material will support sciatic nerve regeneration over a critical gap defect.

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Dose-dependent facilitation of peripheral nerve regeneration by bone marrow–derived mononuclear cells: a randomized controlled study

Journal of Neurosurgery ◽

10.3171/2012.8.jns111446 ◽

2012 ◽

Vol 117 (6) ◽

pp. 1170-1181 ◽

Cited By ~ 15

Author(s):

Amol Raheja ◽

Vaishali Suri ◽

Ashish Suri ◽

Chitra Sarkar ◽

Arti Srivastava ◽

...

Keyword(s):

Bone Marrow ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Mononuclear Cells ◽

Peripheral Nerve Regeneration ◽

Control Group ◽

High Dose ◽

Myelin Thickness ◽

Dose Dependent

Object Bone marrow–derived stem cells enhance the rate of regeneration of neuronal cells leading to clinical improvement in nerve injury, spinal cord injury, and brain infarction. Recent experiments in the local application of bone marrow–derived mononuclear cells (BM-MNCs) in models of sciatic nerve transection in rats have suggested their beneficial role in nerve regeneration, although the effects of variable doses of stem cells on peripheral nerve regeneration have never been specifically evaluated in the literature. In this paper, the authors evaluated the dose-dependent role of BM-MNCs in peripheral nerve regeneration in a model of sciatic nerve transection in rats. Methods The right sciatic nerve of 60 adult female Wistar rats (randomized into 2 test groups and 1 control group, 20 rats in each group) underwent transection under an operating microscope. The cut ends of the nerve were approximated using 2 epineural microsutures. The gap was filled with low-dose (5 million BM-MNCs/100 μl phosphate-buffered saline [PBS]) rat BM-MNCs in one group, high-dose (10 million BM-MNCs/100 μl PBS) rat BM-MNCs in another group, and only PBS in the control group, and the approximated nerve ends were sealed using fibrin glue. Histological assessment was performed after 30 days by using semiquantitative and morphometric analyses and was done to assess axonal regeneration, percentage of myelinated fibers, axonal diameter, fiber diameter, and myelin thickness at distal-most sites (10 mm from site of repair), intermediate distal sites (5 mm distal to the repair site), and site of repair. Results The recovery of nerve cell architecture after nerve anastomosis was far better in the high-dose BM-MNC group than in the low-dose BM-MNC and control groups, and it was most evident (p < 0.02 in the majority of the parameters [3 of 4]) at the distal-most site. Overall, the improvement in myelin thickness was most significant with incremental dosage of BM-MNCs, and was evident at the repair, intermediate distal, and distal-most sites (p = 0.001). Conclusions This study emphasizes the role of BM-MNCs, which can be isolated easily from bone marrow aspirates, in peripheral nerve injury and highlights their dose-dependent facilitation of nerve regeneration.

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

Molecular Brain ◽

10.1186/s13041-019-0516-6 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 4

Author(s):

Hongkui Wang ◽

Ping Zhang ◽

Jun Yu ◽

Fuchao Zhang ◽

Wenzhao Dai ◽

...

Keyword(s):

Cell Migration ◽

Sciatic Nerve ◽

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Schwann Cell Migration

AbstractSchwann 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.

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