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.

scholarly journals Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves

2015 ◽  
Vol 210 (1) ◽  
pp. 153-168 ◽  
Author(s):  
Jose A. Gomez-Sanchez ◽  
Lucy Carty ◽  
Marta Iruarrizaga-Lejarreta ◽  
Marta Palomo-Irigoyen ◽  
Marta Varela-Rey ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Wallerian Degeneration ◽  
Molecular Mechanisms ◽  
Demyelinating Disease ◽  
Cell Reprogramming ◽  
Selective Autophagy ◽  
Wide Range

Although Schwann cell myelin breakdown is the universal outcome of a remarkably wide range of conditions that cause disease or injury to peripheral nerves, the cellular and molecular mechanisms that make Schwann cell–mediated myelin digestion possible have not been established. We report that Schwann cells degrade myelin after injury by a novel form of selective autophagy, myelinophagy. Autophagy was up-regulated by myelinating Schwann cells after nerve injury, myelin debris was present in autophagosomes, and pharmacological and genetic inhibition of autophagy impaired myelin clearance. Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury. We also present evidence that myelinophagy is defective in the injured central nervous system. These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease.

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

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.

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 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 The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration.

1987 ◽  
Vol 165 (4) ◽  
pp. 1218-1223 ◽  
Author(s):  
V H Perry ◽  
M C Brown ◽  
S Gordon
Keyword(s):  
Optic Nerve ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Peripheral Nerve Injury ◽  
Macrophage Response ◽  
Large Numbers ◽  
Myelin Degradation ◽  
Degenerating Axons

Using mAbs and immunocytochemistry we have examined the response of macrophages (M phi) after crush injury to the sciatic or optic nerve in the mouse and rat. We have established that large numbers of M phi enter peripheral nerves containing degenerating axons; the M phi are localized to the portion containing damaged axons, and they phagocytose myelin. The period of recruitment of the M phi in the peripheral nerve is before and during the period of maximal proliferation of the Schwann cells. In contrast, the degenerating optic nerve attracts few M phi, and the removal of myelin is much slower. These results show the clearly different responses of M phi to damage in the central and peripheral nervous systems, and suggest that M phi may be an important component of subsequent repair as well as myelin degradation.

scholarly journals ATP Release through Lysosomal Exocytosis from Peripheral Nerves: The Effect of Lysosomal Exocytosis on Peripheral Nerve Degeneration and Regeneration after Nerve Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Junyang Jung ◽  
Hyun Woo Jo ◽  
Hyunseob Kwon ◽  
Na Young Jeong
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Wallerian Degeneration ◽  
Atp Release ◽  
Nerve Degeneration ◽  
Peripheral Neurons ◽  
Charcot Marie Tooth Disease ◽  
Axonal Degradation

Studies have shown that lysosomal activation increases in Schwann cells after nerve injury. Lysosomal activation is thought to promote the engulfment of myelin debris or fragments of injured axons in Schwann cells during Wallerian degeneration. However, a recent interpretation of lysosomal activation proposes a different view of the phenomenon. During Wallerian degeneration, lysosomes become secretory vesicles and are activated for lysosomal exocytosis. The lysosomal exocytosis triggers adenosine 5′-triphosphate (ATP) release from peripheral neurons and Schwann cells during Wallerian degeneration. Exocytosis is involved in demyelination and axonal degradation, which facilitate nerve regeneration following nerve degeneration. At this time, released ATP may affect the communication between cells in peripheral nerves. In this review, our description of the relationship between lysosomal exocytosis and Wallerian degeneration has implications for the understanding of peripheral nerve degenerative diseases and peripheral neuropathies, such as Charcot-Marie-Tooth disease or Guillain-Barré syndrome.

scholarly journals Practical considerations concerning the use of stem cells for peripheral nerve repair

2009 ◽  
Vol 26 (2) ◽  
pp. E2 ◽  
Author(s):  
Sarah Walsh ◽  
_ _ ◽  
Rajiv Midha
Keyword(s):  
Stem Cells ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Cell Fate ◽  
Peripheral Nerves ◽  
Nerve Repair ◽  
Precursor Cells ◽  
Host Cells ◽  
Injured Nerve

In this review the authors intend to demonstrate the need for supplementing conventional repair of the injured nerve with alternative therapies, namely transplantation of stem or progenitor cells. Although peripheral nerves do exhibit the potential to regenerate axons and reinnervate the end organ, outcome following severe nerve injury, even after repair, remains relatively poor. This is likely because of the extensive injury zone that prevents axon outgrowth. Even if outgrowth does occur, a relatively slow growth rate of regeneration results in prolonged denervation of the distal nerve. Whereas denervated Schwann cells (SCs) are key players in the early regenerative success of peripheral nerves, protracted loss of axonal contact renders Schwann cells unreceptive for axonal regeneration. Given that denervated Schwann cells appear to become effete, one logical approach is to support the distal denervated nerve environment by replacing host cells with those derived exogenously. A number of different sources of stem/precursor cells are being explored for their potential application in the scenario of peripheral nerve injury. The most promising candidate, transplant cells are derived from easily accessible sources such as the skin, bone marrow, or adipose tissue, all of which have demonstrated the capacity to differentiate into Schwann cell–like cells. Although recent studies have shown that stem cells can act as promising and beneficial adjuncts to nerve repair, considerable optimization of these therapies will be required for their potential to be realized in a clinical setting. The authors investigate the relevance of the delivery method (both the number and differentiation state of cells) on experimental outcomes, and seek to clarify whether stem cells must survive and differentiate in the injured nerve to convey a therapeutic effect. As our laboratory uses skin-derived precursor cells (SKPCs) in various nerve injury paradigms, we relate our findings on cell fate to other published studies to demonstrate the need to quantify stem cell survival and differentiation for future studies.

scholarly journals Nogo-C Inhibits Peripheral Nerve Regeneration by Regulating Schwann Cell Apoptosis and Dedifferentiation

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.

scholarly journals Betacellulin Regulates Peripheral Nerve Regeneration by Affecting Schwann Cell Migration and Axon Elongation

2021 ◽  
Author(s):  
Yaxian Wang ◽  
Fuchao Zhang ◽  
Yunsong Zhang ◽  
Qi Shan ◽  
Wei Liu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Cultured Cells ◽  
Axon Elongation ◽  
Schwann Cell Migration

Abstract Background Growth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve injury and regeneration. Our previous sequencing analysis found that betacellulin (Btc), an epidermal growth factor protein family member, showed elevated mRNA expressions in the nerve segment after rat peripheral nerve injury, implying the potential involvement of Btc during peripheral nerve repair. Methods Expression of Btc was examined in Schwann cells. The role of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or exposed cultured cells with Btc recombinant protein, respectively. The biological functions of Schwann cell-secreted Btc on neurons were also determined. Moreover, the in vivo effect of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated.Results Immunostaining images and ELISA readings showed Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that siRNA against Btc impeded Schwann cell migration while exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells might influence neuron behavior and affect axon length. In vivo evidence showed that Btc enhanced axonal regrowth and nerve regeneration after both rat sciatic nerve crush injury and transection injury. Conclusion Our findings demonstrated Btc-mediated Schwann cell-axon interactions, revealed the essential roles of Btc on Schwann cell migration and axon elongation, and implied the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.

The fine structure and morphological organization of non-myelinated nerve fibres

1956 ◽  
Vol 144 (917) ◽  
pp. 496-506 ◽  
Keyword(s):  
Fine Structure ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Myelin Sheath ◽  
Peripheral Nerves ◽  
Nerve Fibres ◽  
Myelinated Nerve ◽  
Morphological Organization ◽  
Myelinated Fibres

The fine structure and morphological organization of non-myelinated nerve fibres were studied by ultra-thin sectioning and electron microscopy in peripheral nerves, autonomic nerves and dorsal roots. Several non-myelinated fibres share the cytoplasm of a Schwann cell. The Schwann cells of non-myelinated fibres form a syncytium. The fibres are incompletely sur­rounded by Schwann cell cytoplasm and are suspended in the cytoplasm by mesaxons formed by the plasma membranes of the Schwann cell. The various relationships of mesaxon and nerve fibre are described. Non-myelinated fibres which do not share a Schwann cell are seen very frequently in the sciatic nerve of a new-born mouse but become less common as myelination proceeds and are rare in adults. It is therefore suggested that in developing peripheral nerves, the non­ myelinated fibres that are destined to myelinate are not organized into groups within a single Schwann cell, even before their myelin sheath has appeared; they are, at least for the ages examined here, individuals in relation to a surrounding individual Schwann cell. It is also suggested that the non-myelinated fibres that will never acquire a myelin sheath are organized in a developing peripheral nerve in the same manner as in the adult nerve—several fibres sharing a single Schwann cell that is part of a syncytial system of Schwann cells. Thus, in a developing peripheral nerve, it appears that two types of non-myelinated fibres are present—one destined to myelinate and lying alone in its own Schwann cell and the other, destined to remain unmyelinated and sharing, along with other non-myelinated fibres of the same type, a Schwann cell. The significance of these observations is discussed in relation to the development of nerve fibres and possible physiological importance.

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