Enhancing Schwann cell migration using concentration gradients of laminin-derived peptides

Motta, Cecilia Margarida Mendes; Endres, Kevin J.; Wesdemiotis, Chrys; Willits, Rebecca Kuntz; Becker, Matthew L.

doi:10.1016/j.biomaterials.2019.119335

Cited by 52 publications

(54 citation statements)

References 81 publications

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“…It has been shown that matrix metalloproteinase 7 (MMP-7) promotes axonal regeneration and remyelination by enhancing SC migration after sciatic nerve injury in rats (Wang H. et al, 2019). In addition, enhancing SC migration using concentration gradients of laminin-derived peptides has been shown to support axonal regeneration over a large nerve gap, further confirming the role of SC migration in axonal regeneration (Motta et al, 2019). Herein, to our surprise, EpoB (1 nM) showed little effect on the viability or apoptosis of SCs, but significantly enhanced SC migration.…”

Section: Discussionmentioning

confidence: 91%

Epothilone B Facilitates Peripheral Nerve Regeneration by Promoting Autophagy and Migration in Schwann Cells

Zhou

Gao

et al. 2020

Front. Cell. Neurosci.

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The search for drugs that can facilitate axonal regeneration and elongation following peripheral nerve injury has been an area of increasing interest in recent years. Epothilone B (EpoB) is an FDA-approved antineoplastic agent, which shows the capacity to induce α-tubulin polymerization and to improve the stability of microtubules. Recently, it has been increasingly recognized that EpoB has a regenerative effect in the central nervous system. However, the information currently available regarding the potential therapeutic effect of EpoB on peripheral nerve regeneration is limited. Here, we used a rat sciatic crush injury model system to determine that EpoB strikingly improved axonal regeneration and recovery of function. Also, EpoB (1 nM) did not result in significant apoptosis in Schwann cells (SCs) and showed little effect on their viability either. Interestingly, EpoB (1 nM) significantly enhanced migration in SCs, which was inhibited by autophagy inhibitors 3-methyladenine (3-MA). Since PI3K/Akt signaling has been implicated in regulating autophagy, we further examined the involvement of PI3K/Akt in the process of EpoB-induced SC migration. We found that EpoB (1 nM) significantly inhibited phosphorylation of PI3K and Akt in SCs. Further studies showed that both EpoB-enhanced migration and autophagy were increased/inhibited by inhibition/activation of PI3K/Akt signaling with LY294002 or IGF-1. In conclusion, EpoB can promote axonal regeneration following peripheral nerve injury by enhancing the migration of SCs, with this activity being controlled by PI3K/Akt signaling-mediated autophagy in SCs. This underscores the potential therapeutic value of EpoB in enhancing regeneration and functional recovery in cases of peripheral nerve injury.

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Section: Discussionmentioning

confidence: 91%

Epothilone B Facilitates Peripheral Nerve Regeneration by Promoting Autophagy and Migration in Schwann Cells

Zhou

Gao

et al. 2020

Front. Cell. Neurosci.

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“…Mann and West [149] fabricated PEG scaffold modified with KQAGDV and demonstrated that such biomaterial enhanced migration, adhesion, and proliferation of smooth muscle cells derived from rat thoracic aorta. In another study, Motta et al [150] presented that RGD, IKVAV, and YIGSR peptides could promote migration, adhesion, and growth of Schwann cells. The authors suggested that these sequences may be useful for modification of scaffolds for nerve regeneration.…”

Section: Presence Of Pro-adhesive Sequencesmentioning

confidence: 98%

Proteins and Peptides as Important Modifiers of the Polymer Scaffolds for Tissue Engineering Applications—A Review

2020

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Polymer scaffolds constitute a very interesting strategy for tissue engineering. Even though they are generally non-toxic, in some cases, they may not provide suitable support for cell adhesion, proliferation, and differentiation, which decelerates tissue regeneration. To improve biological properties, scaffolds are frequently enriched with bioactive molecules, inter alia extracellular matrix proteins, adhesive peptides, growth factors, hormones, and cytokines. Although there are many papers describing synthesis and properties of polymer scaffolds enriched with proteins or peptides, few reviews comprehensively summarize these bioactive molecules. Thus, this review presents the current knowledge about the most important proteins and peptides used for modification of polymer scaffolds for tissue engineering. This paper also describes the influence of addition of proteins and peptides on physicochemical, mechanical, and biological properties of polymer scaffolds. Moreover, this article sums up the major applications of some biodegradable natural and synthetic polymer scaffolds modified with proteins and peptides, which have been developed within the past five years.

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“…LN is secreted by SCs and acts as an adhesive component that promotes the regenerative capacity of basal lamina scaffolds following nerve injury, with previous studies demonstrating its ability to promote neuritogenesis in vitro and in vivo 21 , 22 . Several fragments of the LN sequence were recently identified and tested for their potential bioactivity, with IKVAV (Ile-Lys-Val-Ala-Val) shown to selectively promote SC migration in vitro and capable of easy conjugation to SAPs 23 , 24 . The functional peptide motif IKVAV is commonly used in neurotrophin releasing and stem cell loading during treatment of traumatic brain injury, spinal cord injury, and sciatic nerve injury due to its ability to enhance cell survival and adhesion, neurite outgrowth, and even angiogenesis 25 - 27 .…”

Section: Introductionmentioning

confidence: 99%

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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Enhancing Schwann cell migration using concentration gradients of laminin-derived peptides

Cited by 52 publications

References 81 publications

Epothilone B Facilitates Peripheral Nerve Regeneration by Promoting Autophagy and Migration in Schwann Cells

Epothilone B Facilitates Peripheral Nerve Regeneration by Promoting Autophagy and Migration in Schwann Cells

Proteins and Peptides as Important Modifiers of the Polymer Scaffolds for Tissue Engineering Applications—A Review

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

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