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Journal ArticleDOI

Advances in peripheral nerve regeneration

01 Dec 2013-Nature Reviews Neurology (Nature Publishing Group)-Vol. 9, Iss: 12, pp 668-676
TL;DR: Use of rodent models of chronic denervation will facilitate the understanding of the molecular mechanisms of peripheral nerve regeneration and create the potential to test therapeutic advances.
Abstract: Rodent models of nerve injury have increased our understanding of peripheral nerve regeneration, but clinical applications have been scarce, partly because such models do not adequately recapitulate the situation in humans. In human injuries, axons are often required to extend over much longer distances than in mice, and injury leaves distal nerve fibres and target tissues without axonal contact for extended amounts of time. Distal Schwann cells undergo atrophy owing to the lack of contact with proximal neurons, which results in reduced expression of neurotrophic growth factors, changes in the extracellular matrix and loss of Schwann cell basal lamina, all of which hamper axonal extension. Furthermore, atrophy and denervation-related changes in target tissues make good functional recovery difficult to achieve even when axons regenerate all the way to the target tissue. To improve functional outcomes in humans, strategies to increase the speed of axonal growth, maintain Schwann cells in a healthy, repair-capable state and keep target tissues receptive to reinnervation are needed. Use of rodent models of chronic denervation will facilitate our understanding of the molecular mechanisms of peripheral nerve regeneration and create the potential to test therapeutic advances.
Citations
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Journal ArticleDOI
TL;DR: The transcription factor c‐Jun, although not required for Schwann cell development, is therefore central to the reprogramming of myelin and non‐myelin (Remak) Schwann cells to repair cells after injury.
Abstract: Nerve injury triggers the conversion of myelin and non-myelin (Remak) Schwann cells to a cell phenotype specialized to promote repair. Distal to damage, these repair Schwann cells provide the necessary signals and spatial cues for the survival of injured neurons, axonal regeneration and target reinnervation. The conversion to repair Schwann cells involves de-differentiation together with alternative differentiation, or activation, a combination that is typical of cell type conversions often referred to as (direct or lineage) reprogramming. Thus, injury-induced Schwann cell reprogramming involves down-regulation of myelin genes combined with activation of a set of repair-supportive features, including up-regulation of trophic factors, elevation of cytokines as part of the innate immune response, myelin clearance by activation of myelin autophagy in Schwann cells and macrophage recruitment, and the formation of regeneration tracks, Bungner's bands, for directing axons to their targets. This repair programme is controlled transcriptionally by mechanisms involving the transcription factor c-Jun, which is rapidly up-regulated in Schwann cells after injury. In the absence of c-Jun, damage results in the formation of a dysfunctional repair cell, neuronal death and failure of functional recovery. c-Jun, although not required for Schwann cell development, is therefore central to the reprogramming of myelin and non-myelin (Remak) Schwann cells to repair cells after injury. In future, the signalling that specifies this cell requires further analysis so that pharmacological tools that boost and maintain the repair Schwann cell phenotype can be developed.

728 citations


Cites background from "Advances in peripheral nerve regene..."

  • ...…redundant myelin is removed and new myelin formed around regenerated axons, with the result that nerve tissue that is broadly normal in structure and function is restored in a surprisingly short time, 3–4 weeks (reviewed in Glenn & Talbot, 2013; Scheib & Höke, 2013; Brosius Lutz & Barres, 2014)....

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  • ...…Sons Ltd on behalf of The Physiological Society factor (NGF), vascular endothelial growth factor (VEGF), erythropoietin, pleiotrophin, p75NTR and N-cadherin (Fontana et al. 2012; Brushart et al. 2013; reviewed in Boyd & Gordon, 2003; Chen et al. 2007; Scheib & Höke, 2013; Wood & Mackinnon, 2015)....

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Journal ArticleDOI
TL;DR: This review summarises all the events occurring after nerve damage at the level of the cell body, the site of injury and the target organ.

436 citations


Cites background from "Advances in peripheral nerve regene..."

  • ...rich in trophic factors, enabling guided axonal regeneration [22]....

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Journal ArticleDOI
TL;DR: 3D scaffold fabrication methodologies with a focus on optimizing scaffold performance through the matrix pores, bioactivity and degradation rate to enable tissue regeneration are highlighted.

329 citations


Additional excerpts

  • ...functional recovery difficult to achieve [156]....

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Journal ArticleDOI
TL;DR: The re-programming of Remak and myelin cells to repair cells, together with the injury-induced switch of peripheral neurons to a growth mode, gives peripheral nerves their strong regenerative potential.
Abstract: The remarkable plasticity of Schwann cells allows them to adopt the Remak (non-myelin) and myelin phenotypes, which are specialized to meet the needs of small and large diameter axons, and differ markedly from each other. It also enables Schwann cells initially to mount a strikingly adaptive response to nerve injury and to promote regeneration by converting to a repair-promoting phenotype. These repair cells activate a sequence of supportive functions that engineer myelin clearance, prevent neuronal death, and help axon growth and guidance. Eventually, this response runs out of steam, however, because in the long run the phenotype of repair cells is unstable and their survival is compromised. The re-programming of Remak and myelin cells to repair cells, together with the injury-induced switch of peripheral neurons to a growth mode, gives peripheral nerves their strong regenerative potential. But it remains a challenge to harness this potential and devise effective treatments that maintain the initial repair capacity of peripheral nerves for the extended periods typically required for nerve repair in humans.

268 citations


Cites background from "Advances in peripheral nerve regene..."

  • ...line-derived neurotrophic factor (GDNF), artemin, brainderived neurotrophic factor (BDNF), neurotrophin-3 (NT3), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), erythropoietin, FGFs, pleiotrophin, N-cadherin and p75NTR (Grothe et al., 2006; Fontana et al., 2012; Brushart et al., 2013; reviewed in Boyd and Gordon, 2003; Chen et al., 2007; Scheib and Höke, 2013; Wood and Mackinnon, 2015)....

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Journal ArticleDOI
01 Mar 2019-Glia
TL;DR: The emerging similarities between the injury response seen in nerves and in other tissues are discussed and the transcription factors, epigenetic mechanisms, and signaling cascades that control repair Schwann cells are surveyed, with emphasis on systems that selectively regulate the Schwann cell injury response.
Abstract: Schwann cells respond to nerve injury by cellular reprogramming that generates cells specialized for promoting regeneration and repair. These repair cells clear redundant myelin, attract macrophages, support survival of damaged neurons, encourage axonal growth, and guide axons back to their targets. There are interesting parallels between this response and that found in other tissues. At the cellular level, many other tissues also react to injury by cellular reprogramming, generating cells specialized to promote tissue homeostasis and repair. And at the molecular level, a common feature possessed by Schwann cells and many other cells is the injury-induced activation of genes associated with epithelial-mesenchymal transitions and stemness, differentiation states that are linked to cellular plasticity and that help injury-induced tissue remodeling. The number of signaling systems regulating Schwann cell plasticity is rapidly increasing. Importantly, this includes mechanisms that are crucial for the generation of functional repair Schwann cells and nerve regeneration, although they have no or a minor role elsewhere in the Schwann cell lineage. This encourages the view that selective tools can be developed to control these particular cells, amplify their repair supportive functions and prevent their deterioration. In this review, we discuss the emerging similarities between the injury response seen in nerves and in other tissues and survey the transcription factors, epigenetic mechanisms, and signaling cascades that control repair Schwann cells, with emphasis on systems that selectively regulate the Schwann cell injury response.

188 citations

References
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Journal ArticleDOI
TL;DR: This Review suggests a new grouping of macrophages based on three different homeostatic activities — host defence, wound healing and immune regulation, and proposes that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation.
Abstract: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

7,384 citations

Journal ArticleDOI
TL;DR: Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or “alternatively” activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.
Abstract: Macrophages dominate sites of CNS injury in which they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e., "classically activated" proinflammatory (M1) or "alternatively activated" anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced and then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1/M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or "alternatively" activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.

1,841 citations

Journal ArticleDOI
20 Nov 1981-Science
TL;DR: The origin, termination, and length of axonal growth after focal central nervous system injury was examined in adult rats by means of a new experimental model and the regenerative potential of these central neurons seems to be expressed when the central nervous System glial environment is changed to that of the peripheral nervous system.
Abstract: The origin, termination, and length of axonal growth after focal central nervous system injury was examined in adult rats by means of a new experimental model. When peripheral nerve segments were used as "bridges" between the medulla and spinal cord, axons from neurons at both these levels grew approximately 30 millimeters. The regenerative potential of these central neurons seems to be expressed when the central nervous system glial environment is changed to that of the peripheral nervous system.

1,665 citations

Journal ArticleDOI
TL;DR: The authors would like to include as an addendum the contribution of R. Stout and J. Suttles to the conceptual framework of macrophage plasticity that was mentioned in the Review.
Abstract: Nature Reviews Immunology 8, 958–969 (2008) The authors would like to include as an addendum the contribution of R. Stout and J. Suttles to the conceptual framework of macrophage plasticity that was mentioned in our Review. Their ideas on the ability of macrophages to change their functional phenotype in response to their tissue environment were previously published in two review articles (J.

1,523 citations