Therapeutic Low-Intensity Ultrasound for Peripheral Nerve Regeneration – A Schwann Cell Perspective

Peripheral nerve injuries are common conditions that can arise from trauma (e.g., compression, severance) and can lead to neuropathic pain as well as motor and sensory deficits. Although much knowledge exists on the mechanisms of injury and nerve regeneration, treatments that ensure functional recovery following peripheral nerve injury are limited. Schwann cells, the supporting glial cells in peripheral nerves, orchestrate the response to nerve injury, by converting to a “repair” phenotype. However, nerve regeneration is often suboptimal in humans as the repair Schwann cells do not sustain their repair phenotype long enough to support the prolonged regeneration times required for successful nerve regrowth. Thus, numerous strategies are currently focused on promoting and extending the Schwann cells repair phenotype. Low-intensity ultrasound (LIU) is a non-destructive therapeutic approach which has been shown to facilitate peripheral nerve regeneration following nerve injury in rodents. Still, clinical trials in humans are scarce and limited to small population sizes. The benefit of LIU on nerve regeneration could possibly be mediated through the repair Schwann cells. In this review, we discuss the known and possible molecular mechanisms activated in response to LIU in repair Schwann cells to draw support and attention to LIU as a compelling regenerative treatment for peripheral nerve injury.

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The effects of low-intensity ultrasound on peripheral nerve regeneration in poly(dl-lactic acid-co-glycolic acid) conduits seeded with Schwann cells

Ultrasound in Medicine & Biology ◽

10.1016/j.ultrasmedbio.2004.06.005 ◽

2004 ◽

Vol 30 (8) ◽

pp. 1079-1084 ◽

Cited By ~ 38

Author(s):

Chen-Jung Chang ◽

Shan-Hui Hsu

Keyword(s):

Lactic Acid ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Glycolic Acid ◽

Peripheral Nerve Regeneration ◽

Low Intensity ◽

Low Intensity Ultrasound

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Nerve Suture Combined With ADSCs Injection Under Real-Time and Dynamic NIR-II Fluorescence Imaging in Peripheral Nerve Regeneration in vivo

Frontiers in Chemistry ◽

10.3389/fchem.2021.676928 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shixian Dong ◽

Sijia Feng ◽

Yuzhou Chen ◽

Mo Chen ◽

Yimeng Yang ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Real Time ◽

Fluorescence Imaging ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Post Injection ◽

Nerve Suture

Peripheral nerve injury gives rise to devastating conditions including neural dysfunction, unbearable pain and even paralysis. The therapeutic effect of current treatment for peripheral nerve injury is unsatisfactory, resulting in slow nerve regeneration and incomplete recovery of neural function. In this study, nerve suture combined with ADSCs injection was adopted in rat model of sciatic nerve injury. Under real-time visualization of the injected cells with the guidance of NIR-II fluorescence imaging in vivo, a spatio-temporal map displaying cell migration from the proximal injection site (0 day post-injection) of the nerve to the sutured site (7 days post-injection), and then to the distal section (14 days post-injection) was demonstrated. Furthermore, the results of electromyography and mechanical pain threshold indicated nerve regeneration and functional recovery after the combined therapy. Therefore, in the current study, the observed ADSCs migration in vivo, electrophysiological examination results and pathological changes all provided robust evidence for the efficacy of the applied treatment. Our approach of nerve suture combined with ADSCs injection in treating peripheral nerve injury under real-time NIR-II imaging monitoring in vivo added novel insights into the treatment for peripheral nerve injury, thus further enhancing in-depth understanding of peripheral nerve regeneration and the mechanism behind.

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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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XT-type DNA Hydrogels Loaded with VEGF and NGF Promote Peripheral Nerve Regeneration via Biphasic Release Profile

Biomaterials Science ◽

10.1039/d1bm01377g ◽

2021 ◽

Author(s):

Songyang Liu ◽

Yijun Liu ◽

Liping Zhou ◽

Ci Li ◽

Meng Zhang ◽

...

Keyword(s):

Tissue Engineering ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Release Profile ◽

Nerve Conduits ◽

Biomaterial Science ◽

Biphasic Release

Peripheral nerve injury (PNI) remains an unresolved challenge in the medicine area. With the development of biomaterial science and tissue engineering, a variety of nerve conduits were widely applied in...

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Proliferative effects of melatonin on Schwann cells: implication for nerve regeneration following peripheral nerve injury

Journal of Pineal Research ◽

10.1111/jpi.12125 ◽

2014 ◽

Vol 56 (3) ◽

pp. 322-332 ◽

Cited By ~ 27

Author(s):

Hung-Ming Chang ◽

Chiung-Hui Liu ◽

Wen-Ming Hsu ◽

Li-You Chen ◽

Han-Pin Wang ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Nerve Injury ◽

Peripheral Nerve Injury

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

Cell Death and Disease ◽

10.1038/s41419-021-03706-8 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Qianqian Chen ◽

Qianyan Liu ◽

Yunsong Zhang ◽

Shiying Li ◽

Sheng Yi

Keyword(s):

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Nerve Injury ◽

Peripheral Nerves ◽

Leukemia Inhibitory Factor ◽

Peripheral Nerve Regeneration ◽

And Migration ◽

Proliferation And Migration

AbstractLeukemia 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.

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

Scientific Reports ◽

10.1038/srep39869 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 18

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.

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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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Recruitment by SDF-1α of CD34-positive cells involved in sciatic nerve regeneration

Journal of Neurosurgery ◽

10.3171/2011.3.jns101582 ◽

2012 ◽

Vol 116 (2) ◽

pp. 432-444 ◽

Cited By ~ 12

Author(s):

Meei-Ling Sheu ◽

Fu-Chou Cheng ◽

Hong-Lin Su ◽

Ying-Ju Chen ◽

Chun-Jung Chen ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Neurological Function ◽

Crush Injury ◽

Local Application ◽

Angiogenesis Factors

Object Increased integration of CD34+ cells in injured nerve significantly promotes nerve regeneration, but this effect can be counteracted by limited migration and short survival of CD34+ cells. SDF-1α and its receptor mediate the recruitment of CD34+ cells involved in the repair mechanism of several neurological diseases. In this study, the authors investigate the potentiation of CD34+ cell recruitment triggered by SDF-1α and the involvement of CD34+ cells in peripheral nerve regeneration. Methods Peripheral nerve injury was induced in 147 Sprague-Dawley rats by crushing the left sciatic nerve with a vessel clamp. The animals were allocated to 3 groups: Group 1, crush injury (controls); Group 2, crush injury and local application of SDF-1α recombinant proteins; and Group 3, crush injury and local application of SDF-1α antibody. Electrophysiological studies and assessment of regeneration markers were conducted at 4 weeks after injury; neurobehavioral studies were conducted at 1, 2, 3, and 4 weeks after injury. The expression of SDF-1α, accumulation of CD34+ cells, immune cells, and angiogenesis factors in injured nerves were evaluated at 1, 3, 7, 10, 14, 21, and 28 days after injury. Results Application of SDF-1α increased the migration of CD34+ cells in vitro, and this effect was dose dependent. Crush injury induced the expression of SDF-1α, with a peak of 10–14 days postinjury, and this increased expression of SDF-1α paralleled the deposition of CD34+ cells, expression of VEGF, and expression of neurofilament. These effects were further enhanced by the administration of SDF-1α recombinant protein and abolished by administration of SDF-1α antibody. Furthermore, these effects were consistent with improvement in measures of neurological function such as sciatic function index, electrophysiological parameters, muscle weight, and myelination of regenerative nerve. Conclusions Expression of SDF-1α facilitates recruitment of CD34+ cells in peripheral nerve injury. The increased deposition of CD34+ cells paralleled significant expression of angiogenesis factors and was consistent with improvement of neurological function. Utilization of SDF-1α for enhancing the recruitment of CD34+ cells involved in peripheral nerve regeneration may be considered as an alternative treatment strategy in peripheral nerve disorders.

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