scholarly journals Loss of Sarm1 non-autonomously protects Schwann cells from chemotoxicity

2018 ◽  
Author(s):  
Weili Tian ◽  
Tim Czopka ◽  
Hernán López-Schier
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Nerve Repair ◽  
Chemotherapeutic Agents ◽  
Axon Degeneration ◽  
Effective Strategy ◽  
Cell Resistance ◽  
Neuroprotective Strategy ◽  
Focal Injury ◽  
Severed Axons

ABSTRACTThe obligate pro-degenerative protein Sarm1 is essential for Wallerian axon degeneration. Inhibition of Sarm1 has been proposed as a promising neuroprotective strategy with clinical relevance. Yet, the conditions that will most benefit from inhibiting Sarm1 remain undefined. Here we use genetics and pharmacology in zebrafish to show that systemic elimination of Sarm1 is glioprotective. Loss of Sarm1 does not affect macrophage recruitment to the wound microenvironment, focal injury resolution, or nerve repair. Unexpectedly, Sarm1 deficiency increases Schwann-cell resistance to toxicity by diverse chemotherapeutic agents after neuronal injury. Yet, synthetic degradation of Sarm1-deficient severed axons reversed this effect, suggesting that glioprotection is non-cell-autonomous. These findings anticipate that interventions aimed at inhibiting Sarm1 can counter heightened glial vulnerability to chemical stressors and may be an effective strategy to reduce chronic consequences of neurotrauma.

scholarly journals Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Laura J Wagstaff ◽  
Jose A Gomez-Sanchez ◽  
Shaline V Fazal ◽  
Georg W Otto ◽  
Alastair M Kilpatrick ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Nerve Repair ◽  
Axon Growth ◽  
Common Mechanism ◽  
Molecular Pathways ◽  
Chronic Denervation ◽  
Clinical Problems ◽  
Molecular Framework

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.

Hierarchical thermoplastic rippled nanostructures regulate Schwann cell adhesion, morphology and spatial organization

Nanoscale ◽  
2017 ◽  
Vol 9 (39) ◽  
pp. 14861-14874 ◽  
Author(s):  
Cecilia Masciullo ◽  
Rossana Dell'Anna ◽  
Ilaria Tonazzini ◽  
Roman Böettger ◽  
Giancarlo Pepponi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Spatial Organization ◽  
Nerve Repair

Hierarchical rippled nanotopographies are produced in PET. The effects of these nano-ripples on Schwann Cells are studied for nerve-repair applications.

scholarly journals Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

2021 ◽  
Vol 13 ◽  
Author(s):  
Anjali Balakrishnan ◽  
Lauren Belfiore ◽  
Tak-Ho Chu ◽  
Taylor Fleming ◽  
Rajiv Midha ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Schwann Cells ◽  
Molecular Mechanisms ◽  
Nerve Repair ◽  
Motor Deficits ◽  
Repair Capacity ◽  
Peripheral Nerve Repair ◽  
Cell Replacement

Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.

scholarly journals Evaluation of Epigallocatechin-3-gallate Modified Collagen Membrane and Concerns on Schwann Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Chenyu Chu ◽  
Jia Deng ◽  
Cong Cao ◽  
Yi Man ◽  
Yili Qu
Keyword(s):  
Cell Proliferation ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Biological Activities ◽  
Nerve Repair ◽  
Fracture Repair ◽  
Cell Counting ◽  
Enzyme Linked Immunosorbent Assay ◽  
Collagen Membrane ◽  
Proliferation And Differentiation

Collagen is an essential component of the extracellular matrix (ECM) and is a suitable material for nerve repair during tissue remodeling for fracture repair. Epigallocatechin-3-gallate (EGCG), an extract of green tea, shows various biological activities that are beneficial to nerve repair. Here, we developed modified collagen containing different concentrations of EGCG (0.0064%, 0.064%, and 0.64%, resp.) to induce Schwann cell proliferation and differentiation. Cell Counting Kit-8 test, live/dead assay, and SEM showed that collagen cross-linked by EGCG induced Schwann cell proliferation. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting revealed that EGCG-modified collagen induced Schwann cell differentiation and downregulated reactive oxygen species (ROS) levels by downregulating the MAPK P38 signaling pathway. Our results indicate that collagen cross-linked with an appropriate concentration of EGCG induces the proliferation and differentiation of Schwann cells. The EGCG-modified collagen membrane may be applicable for nerve repair and guided tissue regeneration applications.

scholarly journals Axon-dependent expression of YAP/TAZ mediates Schwann cell remyelination but not proliferation after nerve injury

2019 ◽  
Author(s):  
Matthew Grove ◽  
Hyunkyoung Lee ◽  
Huaqing Zhao ◽  
Young-Jin Son
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Myelin Sheath ◽  
Transcriptional Activity ◽  
Axon Degeneration ◽  
Adult Mice ◽  
Functional Regeneration ◽  
Growth Promoting

ABSTRACTPreviously we showed that YAP/TAZ promote not only proliferation but also differentiation of immature Schwann cells (SCs), thereby forming and maintaining the myelin sheath around peripheral axons (Grove et al., 2017). Here we show that YAP/TAZ are required for mature SCs to restore peripheral myelination, but not to proliferate, after nerve injury. We find that YAP/TAZ dramatically disappear from SCs of adult mice concurrent with axon degeneration after nerve injury. They reappear in SCs only if axons regenerate. YAP/TAZ ablation does not impair SC proliferation or transdifferentiation into growth promoting repair SCs. SCs lacking YAP/TAZ, however, fail to upregulate myelin-associated genes and completely fail to remyelinate regenerated axons. We also show that both YAP and TAZ are redundantly required for optimal remyelination. These findings suggest that axons regulate transcriptional activity of YAP/TAZ in adult SCs and that YAP/TAZ are essential for functional regeneration of peripheral nerve.

scholarly journals Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

2020 ◽  
Author(s):  
Laura J. Wagstaff ◽  
Jose A. Gomez-Sanchez ◽  
Shaline V. Fazal ◽  
Georg W. Otto ◽  
Alastair M. Kilpatrick ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Slow Growth ◽  
Nerve Repair ◽  
Clinical Problem ◽  
Common Mechanism ◽  
Chronic Denervation ◽  
Clinical Problems ◽  
Molecular Framework

ABSTRACTAfter nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from the slow growth of axons. This impairs axonal regeneration and causes a significant clinical problem. In mice, we find that repair cells express reduced c-Jun protein as the regenerative support provided by these cells declines in aging animals and during chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates the success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, and suggests molecular pathways that can be targeted to promote repair in the PNS.

Autologous adult human Schwann cells genetically modified to provide alternative cellular transplants in peripheral nerve regeneration

2006 ◽  
Vol 104 (5) ◽  
pp. 778-786 ◽  
Author(s):  
Kirsten Haastert ◽  
Christina Mauritz ◽  
Cordula Matthies ◽  
Claudia Grothe
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Cell Cultures ◽  
Genetically Modified ◽  
Nerve Repair ◽  
Peripheral Nerve Regeneration ◽  
Nerve Biopsy ◽  
Culture Conditions ◽  
Adult Human

Object The purpose of this study was to provide genetically modified adult human Schwann cells as tools for cell transplantation in peripheral nerve repair. The application of transfected autologous Schwann cells overexpressing regeneration-promoting proteins, for example, neurotrophic or growth factors, is a promising approach in the aforementioned context. To achieve an optimal clinical outcome, it is highly important to perform enrichment, genetic modification, and retransplantation of cells in a short time. Methods To enable the development of these autologous cellular prostheses, the authors tested the properties of adult human Schwann cells obtained from differently treated human peripheral nerve biopsy samples. The use of “cold jet,” a fast and effective enrichment procedure, as well as selective, serum-free culture conditions, resulted in very pure adult human Schwann cell cultures. Using an optimized electroporation protocol, as many as 48.4% of adult human Schwann cells were successfully transfected. Conclusions The authors present a very fast protocol to establish adult human Schwann cell cultures that demonstrably express plasmid proteins after plasmid DNA insertion by electroporation. These autologous human Schwann cells transfected to enhance the endogenous production of regeneration-supporting proteins will likely constitute a major component of tissue-engineered peripheral nerve grafts.

Schwann Cell Strip for Peripheral Nerve Repair

2008 ◽  
Vol 33 (5) ◽  
pp. 587-594 ◽  
Author(s):  
D. F. KALBERMATTEN ◽  
P. ERBA ◽  
D. MAHAY ◽  
M. WIBERG ◽  
G. PIERER ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Fibrin Glue ◽  
Nerve Repair ◽  
Group Versus ◽  
Nerve Graft ◽  
Nerve Grafting ◽  
New Approach ◽  
Nerve Fascicle ◽  
Small Nerve

Many strategies have been investigated to provide an ideal substitute to treat a nerve gap injury. Initially, silicone conduits were used and more recently conduits fabricated from natural materials such as poly-3-hydroxybutyrate (PHB) showed good results but still have their limitations. Surgically, a new concept optimising harvested autologous nerve graft has been introduced as the single fascicle method. It has been shown that a single fascicle repair of nerve grafting is successful. We investigated a new approach using a PHB strip seeded with Schwann cells to mimic a small nerve fascicle. Schwann cells were attached to the PHB strip using diluted fibrin glue and used to bridge a 10-mm sciatic nerve gap in rats. Comparison was made with a group using conventional PHB conduit tubes filled with Schwann cells and fibrin glue. After 2 weeks, the nerve samples were harvested and investigated for axonal and Schwann cell markers. PGP9.5 immunohistochemistry showed a superior nerve regeneration distance in the PHB strip group versus the PHB tube group (> 10 mm, crossed versus 3.17± 0.32 mm respectively, P<0.05) as well as superior Schwann cell intrusion (S100 staining) from proximal (> 10 mm, crossed versus 3.40± 0.36 mm, P<0.01) and distal (> 10 mm, crossed versus 2.91± 0.31 mm, P<0.001) ends. These findings suggest a significant advantage of a strip in rapidly connecting a nerve gap lesion and imply that single fascicle nerve grafting is advantageous for nerve repair in rats.

scholarly journals Axon-dependent expression of YAP/TAZ mediates Schwann cell remyelination but not proliferation after nerve injury

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Matthew Grove ◽  
Hyunkyoung Lee ◽  
Huaqing Zhao ◽  
Young-Jin Son
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Myelin Sheath ◽  
Transcriptional Activity ◽  
Axon Degeneration ◽  
Adult Mice ◽  
Functional Regeneration ◽  
Growth Promoting

Previously we showed that YAP/TAZ promote not only proliferation but also differentiation of immature Schwann cells (SCs), thereby forming and maintaining the myelin sheath around peripheral axons (Grove et al., 2017). Here we show that YAP/TAZ are required for mature SCs to restore peripheral myelination, but not to proliferate, after nerve injury. We find that YAP/TAZ dramatically disappear from SCs of adult mice concurrent with axon degeneration after nerve injury. They reappear in SCs only if axons regenerate. YAP/TAZ ablation does not impair SC proliferation or transdifferentiation into growth promoting repair SCs. SCs lacking YAP/TAZ, however, fail to upregulate myelin-associated genes and completely fail to remyelinate regenerated axons. We also show that both YAP and TAZ are redundantly required for optimal remyelination. These findings suggest that axons regulate transcriptional activity of YAP/TAZ in adult SCs and that YAP/TAZ are essential for functional regeneration of peripheral nerve.

scholarly journals Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

2021 ◽  
Author(s):  
Peter Arthur-Farraj ◽  
Michael P. Coleman
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Molecular Mechanisms ◽  
Axon Degeneration ◽  
Axon Loss ◽  
Factor C ◽  
Inherited Neuropathies

AbstractSince Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell. We discuss how nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha TIR motif containing protein 1 (SARM1) are required for axon survival and degeneration, respectively, how transcription factor c-JUN is essential for the Schwann cell response to nerve injury and what each tells us about disease mechanisms and potential therapies. Human genetic association with NMNAT2 and SARM1 strongly suggests aberrant activation of programmed axon death in polyneuropathies and motor neuron disorders, respectively, and animal studies suggest wider involvement including in chemotherapy-induced and diabetic neuropathies. In repair Schwann cells, cJUN is aberrantly expressed in a wide variety of human acquired and inherited neuropathies. Animal models suggest it limits axon loss in both genetic and traumatic neuropathies, whereas in contrast, Schwann cell secreted Neuregulin-1 type 1 drives onion bulb pathology in CMT1A. Finally, we discuss opportunities for drug-based and gene therapies to prevent axon loss or manipulate the repair Schwann cell state to treat acquired and inherited neuropathies and neuronopathies.

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