GDNF pretreatment overcomes Schwann cell phenotype mismatch to promote motor axon regeneration via sensory graft

Fang, Xinyu; Zhang, Chaofan; Yu, Zibo; Li, Wenbo; Huang, Zida; Zhang, Wenming

doi:10.1016/j.expneurol.2019.05.011

Cited by 13 publications

(12 citation statements)

References 44 publications

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“…The secretion of NGF and BDNF, and the myelination were considered as the function of SCs. Therefore, here we only discussed the effect of hydrogels on SCs after 7 days, which was similar to previous study 78 . However, more investigation about the relationship between cell types and gene expression in vivo should be carried out.…”

Section: Discussionmentioning

confidence: 60%

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

et al. 2020

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The regenerative capacity of the peripheral nervous system is closely related to the role that Schwann cells (SCs) play in construction of the basement membrane containing multiple extracellular matrix proteins and secretion of neurotrophic factors, including laminin (LN) and brain-derived neurotrophic factor (BDNF). Here, we developed a self-assembling peptide (SAP) nanofiber hydrogel based on self-assembling backbone Ac-(RADA) 4 -NH 2 (RAD) dual-functionalized with laminin-derived motif IKVAV (IKV) and a BDNF-mimetic peptide epitope RGIDKRHWNSQ (RGI) for peripheral nerve regeneration, with the hydrogel providing a three-dimensional (3D) microenvironment for SCs and neurites. Methods: Circular dichroism (CD), atomic force microscopy (AFM), and scanning electron microscopy (SEM) were used to characterize the secondary structures, microscopic structures, and morphologies of self-assembling nanofiber hydrogels. Then the SC adhesion, myelination and neurotrophin secretion were evaluated on the hydrogels. Finally, the SAP hydrogels were injected into hollow chitosan tubes to bridge a 10-mm-long sciatic nerve defect in rats, and in vivo gene expression at 1 week, axonal regeneration, target muscular re-innervation, and functional recovery at 12 weeks were assessed. Results: The bioactive peptide motifs were covalently linked to the C-terminal of the self-assembling peptide and the functionalized peptides could form well-defined nanofibrous hydrogels capable of providing a 3D microenvironment similar to native extracellular matrix. SCs displayed improved cell adhesion on hydrogels with both IKV and RGI, accompanied by increased cell spreading and elongation relative to other groups. RSCs cultured on hydrogels with IKV and RGI showed enhanced gene expression of NGF, BDNF, CNTF, PMP22 and NRP2, and decreased gene expression of NCAM compared with those cultured on other three groups after a 7-day incubation. Additionally, the secretion of NGF, BDNF, and CNTF of RSCs was significantly improved on dual-functionalized peptide hydrogels after 3 days. At 1 week after implantation, the expressions of neurotrophin and myelin-related genes in the nerve grafts in SAP and Autograft groups were higher than that in Hollow group, and the expression of S100 in groups containing both IKV and RGI was significantly higher than that in groups containing either IKV or RGI hydrogels, suggesting enhanced SC proliferation. The morphometric parameters of the regenerated nerves, their electrophysiological performance, the innervated muscle weight and remodeling of muscle fibers, and motor function showed that RAD/IKV/RGI and RAD/IKV-GG-RGI hydrogels could markedly improve axonal regeneration with enhanced re-myelination and motor functional recovery through the synergetic effect of IKV and RGI functional motifs. Conclusions: We found that the dual-functionalized SAP hydrogels promoted RSC adhesion, my...

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Section: Discussionmentioning

confidence: 60%

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

et al. 2020

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“…A similar enhancement of motor axon regeneration was found after treating a denervated saphenous nerve with GDNF and grafting it to the muscle branch of the femoral nerve. Motoneurons were able to regenerate in the pretreated sensory grafts to the same extent as in the positive control (denervated quadriceps nerve graft) and significantly better than in sensory grafts without the GDNF treatment [ 75 ]. The mechanism by which this trophic factor presumably enhances specific regeneration is unclear.…”

Section: Motor and Sensory Schwann Cellsmentioning

confidence: 99%

“…The mechanism by which this trophic factor presumably enhances specific regeneration is unclear. GDNF seems to promote SC differentiation to their original phenotype [ 75 , 76 ], but this would increase the effect of phenotype mismatch and, thus, most likely hinder motor axon regeneration. This exogenous GDNF also stimulates endogenous GDNF production in SCs [ 73 , 75 ] by a positive-feedback mechanism, and perhaps this overall increase in GDNF and other trophic factors, such as BDNF [ 75 , 76 ], is responsible for the enhanced axonal regeneration.…”

Section: Motor and Sensory Schwann Cellsmentioning

confidence: 99%

Schwann Cell Role in Selectivity of Nerve Regeneration

Bolívar

Navarro

Udina

2020

Cells

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Peripheral nerve injuries result in the loss of the motor, sensory and autonomic functions of the denervated segments of the body. Neurons can regenerate after peripheral axotomy, but inaccuracy in reinnervation causes a permanent loss of function that impairs complete recovery. Thus, understanding how regenerating axons respond to their environment and direct their growth is essential to improve the functional outcome of patients with nerve lesions. Schwann cells (SCs) play a crucial role in the regeneration process, but little is known about their contribution to specific reinnervation. Here, we review the mechanisms by which SCs can differentially influence the regeneration of motor and sensory axons. Mature SCs express modality-specific phenotypes that have been associated with the promotion of selective regeneration. These include molecular markers, such as L2/HNK-1 carbohydrate, which is differentially expressed in motor and sensory SCs, or the neurotrophic profile after denervation, which differs remarkably between SC modalities. Other important factors include several molecules implicated in axon-SC interaction. This cell–cell communication through adhesion (e.g., polysialic acid) and inhibitory molecules (e.g., MAG) contributes to guiding growing axons to their targets. As many of these factors can be modulated, further research will allow the design of new strategies to improve functional recovery after peripheral nerve injuries.

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“…Animals were provided by the Laboratory Animal Unit at Fujian Medical University. We followed the methodology of our previously published work [13, 18, 19].…”

Section: Methodsmentioning

confidence: 99%

Reactivation of Denervated Schwann Cells by Embryonic Spinal Cord Neurons to Promote Axon Regeneration and Remyelination

Fang

Zhang

et al. 2019

Stem Cells International

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In peripheral nerve injuries (PNIs) in which proximal axons do not regenerate quickly enough, significant chronic degeneration of Schwann cells (SCs) can occur at the distal stump of the injured nerve and obstruct regeneration. Cell transplantation can delay the degeneration of SCs, but transplanted cells fail to generate voluntary electrical impulses without downstream signal stimulation from the central nervous system. In this study, we combined cell transplantation and nerve transfer strategies to investigate whether the transplantation of embryonic spinal cord cells could benefit the microenvironment of the distal stump of the injured nerve. The experiment consisted of two stages. In the first-stage surgery, common peroneal nerves were transected, and embryonic day 14 (E14) cells or cell culture medium was transplanted into the distal stump of the CPs. Six months after the first-stage surgery, the transplanted cells were removed, and the nerve segment distal to the transplanted site was used to bridge freshly cut tibial nerves to detect whether the cell-treated graft promoted axon growth. The phenotypic changes and the neurotrophic factor expression pattern of SCs distal to the transplanted site were detected at several time points after cell transplantation and excision. The results showed that at different times after transplantation, the cells could survive and generate neurons. Thus, the neurons play the role of proximal axons to prevent chronic degeneration and fibrosis of SCs. After excision of the transplanted cells, the SCs returned to their dedifferentiated phenotype and upregulated growth-associated gene expression. The ability of SCs to be activated again allowed a favorable microenvironment to be created and enhanced the regeneration and remyelination of proximal axons. Muscle reinnervation was also elevated. This transplantation strategy could provide a treatment option for complex neurological injuries in the clinic.

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GDNF pretreatment overcomes Schwann cell phenotype mismatch to promote motor axon regeneration via sensory graft

Cited by 13 publications

References 44 publications

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

Schwann Cell Role in Selectivity of Nerve Regeneration

Reactivation of Denervated Schwann Cells by Embryonic Spinal Cord Neurons to Promote Axon Regeneration and Remyelination

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