Fibroblasts Colonizing Nerve Conduits Express High Levels of Soluble Neuregulin1, a Factor Promoting Schwann Cell Dedifferentiation

Conduits for the repair of peripheral nerve gaps are a good alternative to autografts as they provide a protected environment and a physical guide for axonal re-growth. Conduits require colonization by cells involved in nerve regeneration (Schwann cells, fibroblasts, endothelial cells, macrophages) while in the autograft many cells are resident and just need to be activated. Since it is known that soluble Neuregulin1 (sNRG1) is released after injury and plays an important role activating Schwann cell dedifferentiation, its expression level was investigated in early regeneration steps (7, 14, 28 days) inside a 10 mm chitosan conduit used to repair median nerve gaps in Wistar rats. In vivo data show that sNRG1, mainly the isoform α, is highly expressed in the conduit, together with a fibroblast marker, while Schwann cell markers, including NRG1 receptors, were not. Primary culture analysis shows that nerve fibroblasts, unlike Schwann cells, express high NRG1α levels, while both express NRG1β. These data suggest that sNRG1 might be mainly expressed by fibroblasts colonizing nerve conduit before Schwann cells. Immunohistochemistry analysis confirmed NRG1 and fibroblast marker co-localization. These results suggest that fibroblasts, releasing sNRG1, might promote Schwann cell dedifferentiation to a “repair” phenotype, contributing to peripheral nerve regeneration.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Resorbable Structures for Schwann Cell Enhanced Peripheral Nerve Regeneration

MRS Proceedings ◽

10.1557/proc-550-297 ◽

1998 ◽

Vol 550 ◽

Cited By ~ 1

Author(s):

A.E. Silva ◽

LC. Summerhayes ◽

D.J. Trantolo ◽

D.L. Wise ◽

M.V. Catftaneo ◽

...

Keyword(s):

Growth Factor ◽

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Peripheral Nerve Regeneration ◽

Cell Movement ◽

Regenerative Process

AbstractSchwann cells play a dual role serving as a physical framework for regenerating nerves, providing extracellular matrix proteins and specific adhesion molecules facilitating attachment and cell movement, and as a source of stimulatory factors mediated by the release or reception of different ligands important in growth and cell signaling events. To investigate the role of one such ligand, glial growth factor (GGF), in peripheral nerve regeneration, a bioabsorbable nerve guide, prepared from a poly(lactic-co-glycolic) acid (PLGA) foam was seeded with autogenous Schwann cells in the presence and absence of growth factor and evaluated in vivo using a rat sciatic nerve regeneration model. Four weeks post-operatively peripheral nerve regeneration was evident. The resorbable foam implant demonstrated extensive neo-vascularization in and around the guide with no evidence of an inflammatory response or encapsulation. The study showed a statistically significant increase in all measured parameters of nerve regeneration in the presence of GGF. Increased numbers of blood vessels in the regenerated tissue accompanied increased total axon counts after twelve weeks. The addition of exogenous Schwann cells resulted in reduced total axon counts perhaps due to the competition for limited growth factors released by the regenerating tissues. The Schwann cell groups, however, displayed the highest myelination indices recorded likely reflecting the role of Schwann cells in the myelination process. Measurements of conduction velocities (EMGs) revealed the highest conductance velocities recorded in nerves regenerated in the presence of both GGF and Schwann cells. Clearly, the inclusion of GGF in the nerve regenerative process is beneficial with respect to both the generation of new axons and the establishment of a functional endpoint.

Download Full-text

Transforming growth factor-? and forskolin attenuate the adverse effects of long-term Schwann cell denervation on peripheral nerve regeneration in vivo

Glia ◽

10.1002/glia.10022 ◽

2002 ◽

Vol 37 (3) ◽

pp. 206-218 ◽

Cited By ~ 64

Author(s):

Olawale A.R. Sulaiman ◽

Tessa Gordon

Keyword(s):

Growth Factor ◽

Adverse Effects ◽

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Transforming Growth Factor ◽

Peripheral Nerve Regeneration

Download Full-text

Human Hair Derived Keratins Mediate Schwann Cell Behavior in vitro and Facilitate Rapid Peripheral Nerve Regeneration in vivo

The FASEB Journal ◽

10.1096/fasebj.21.6.a1273-d ◽

2007 ◽

Vol 21 (6) ◽

Author(s):

Paulina Sierpinski ◽

Jeffrey Garrett ◽

Jianjun Ma ◽

Peter Apel ◽

Tom Smith ◽

...

Keyword(s):

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Human Hair ◽

Peripheral Nerve Regeneration ◽

Cell Behavior

Download Full-text

Single-Lumen and Multi-Lumen Poly(Ethylene Glycol) Nerve Conduits Fabricated by Stereolithography for Peripheral Nerve Regeneration In Vivo

Journal of Reconstructive Microsurgery ◽

10.1055/s-0034-1395415 ◽

2015 ◽

Vol 31 (05) ◽

pp. 327-335 ◽

Cited By ~ 17

Author(s):

Mireya Perez ◽

Ara Salibian ◽

Jeffrey Hassan ◽

Sean Darcy ◽

Keyianoosh Paydar ◽

...

Keyword(s):

Ethylene Glycol ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Peripheral Nerve Regeneration ◽

Poly Ethylene Glycol ◽

Single Lumen ◽

Nerve Conduits ◽

Poly Ethylene

Download Full-text

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.

Download Full-text

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.

Download Full-text