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Plasticity of the Nervous System after Injury

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 25312

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Prof. Dr. Tessa Gordon

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Department of Surgery, Division of Plastic Reconstructive Surgery, 06.9706 Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Interests: nerve injuries; regeneration; neural plasticity; axonal regeneration
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Dear Colleagues,

Functional recovery is too often poor after peripheral nerve injuries. This is in spite of the capacity of supporting glial cells, the Schwann cells that myelinate the axons, to support the regeneration of the injured axons and to reinnervate their target muscle and sense organs. Recovery of function is even more severely limited in the central nervous system. This is due to the inability of the glial cells, oligodendrocytes, to support the growth of central axons. Studies regarding peripheral nerve injuries are revealing recovery mechanisms and novel methodologies to promote functional motor and sensory recovery. These include the activation of intrinsic growth pathways, as well as the use of brief low-frequency electrical stimulation, intermittent hypoxia, bioluminescent optogenetics, optimized nerve grafts and nerve transfers, stem cells, and manufactured Schwann cells for nerve repair. The dynamics of plasticity after spinal cord injuries and the relevance of locomotor networks in restoring function provide a means to restore function after central nerve injuries.

Prof. Dr. Tessa Gordon
Guest Editor

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Published Papers (10 papers)

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Research

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17 pages, 3057 KiB

Open AccessArticle

A Multi-Stage Bioprocess for the Expansion of Rodent Skin-Derived Schwann Cells in Computer-Controlled Bioreactors

by Tylor Walsh, Brett Abraham, Tak-Ho Chu, Jeff Biernaskie, Rajiv Midha and Michael S. Kallos

Int. J. Mol. Sci. 2023, 24(6), 5152; https://doi.org/10.3390/ijms24065152 - 8 Mar 2023

Viewed by 1482

Abstract

Regenerative therapies for the treatment of peripheral nerve and spinal cord injuries can require hundreds of millions of autologous cells. Current treatments involve the harvest of Schwann cells (SCs) from nerves; however, this is an invasive procedure. Therefore, a promising alternative is using skin-derived Schwann cells (Sk-SCs), in which between 3–5 million cells can be harvested from a standard skin biopsy. However, traditional static planar culture is still inefficient at expanding cells to clinically relevant numbers. As a result, bioreactors can be used to develop reproducible bioprocesses for the large-scale expansion of therapeutic cells. Here, we present a proof-of-concept SC manufacturing bioprocess using rat Sk-SCs. With this integrated process, we were able to simulate a feasible bioprocess, taking into consideration the harvest and shipment of cells to a production facility, the generation of the final cell product, and the cryopreservation and shipment of cells back to the clinic and patient. This process started with 3 million cells and inoculated and expanded them to over 200 million cells in 6 days. Following the harvest and post-harvest cryopreservation and thaw, we were able to maintain 150 million viable cells that exhibited a characteristic Schwann cell phenotype throughout each step of the process. This process led to a 50-fold expansion, producing a clinically relevant number of cells in a 500 mL bioreactor in just 1 week, which is a dramatic improvement over current methods of expansion. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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17 pages, 11311 KiB

Open AccessArticle

Repair of Long Peripheral Nerve Defects in Sheep: A Translational Model for Nerve Regeneration

by Estefanía Contreras, Sara Traserra, Sara Bolívar, Joaquím Forés, Eduard Jose-Cunilleras, Ignacio Delgado-Martínez, Félix García, Esther Udina and Xavier Navarro

Int. J. Mol. Sci. 2023, 24(2), 1333; https://doi.org/10.3390/ijms24021333 - 10 Jan 2023

Cited by 7 | Viewed by 2680

Abstract

Despite advances in microsurgery, full functional recovery of severe peripheral nerve injuries is not commonly attained. The sheep appears as a good preclinical model since it presents nerves with similar characteristics to humans. In this study, we induced 5 or 7 cm resection in the peroneal nerve and repaired with an autograft. Functional evaluation was performed monthly. Electromyographic and ultrasound tests were performed at 6.5 and 9 months postoperation (mpo). No significant differences were found between groups with respect to functional tests, although slow improvements were seen from 5 mpo. Electrophysiological tests showed compound muscle action potentials (CMAP) of small amplitude at 6.5 mpo that increased at 9 mpo, although they were significantly lower than the contralateral side. Ultrasound tests showed significantly reduced size of tibialis anterior (TA) muscle at 6.5 mpo and partially recovered size at 9 mpo. Histological evaluation of the grafts showed good axonal regeneration in all except one sheep from autograft 7 cm (AG7) group, while distal to the graft there was a higher number of axons than in control nerves. The results indicate that sheep nerve repair is a useful model for investigating long-gap peripheral nerve injuries. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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14 pages, 2420 KiB

Open AccessArticle

Enhancing Motor and Sensory Axon Regeneration after Peripheral Nerve Injury Using Bioluminescent Optogenetics

by Anna Ecanow, Ken Berglund, Dario Carrasco, Robin Isaacson and Arthur W. English

Int. J. Mol. Sci. 2022, 23(24), 16084; https://doi.org/10.3390/ijms232416084 - 16 Dec 2022

Cited by 6 | Viewed by 2652

Abstract

Introduction—Recovery from peripheral nerve injuries is poor even though injured peripheral axons can regenerate. Novel therapeutic approaches are needed. The most successful preclinical experimental treatments have relied on increasing the activity of the regenerating axons, but the approaches taken are not applicable to many nerve-injured patients. Bioluminescent optogenetics (BL-OG) is a novel method of increasing the excitation of neurons that might be similar to that found with activity-dependent experimental therapies. We investigated the use of BL-OG as an approach to promoting axon regeneration following peripheral nerve injury. Methods—BL-OG uses luminopsins, light-sensing ion channels (opsins) fused with a light-emitting luciferase. When exposed to a luciferase substrate, such as coelenterazine (CTZ), luminopsins expressed in neurons generate bioluminescence and produce excitation through their opsin component. Adeno-associated viral vectors encoding either an excitatory luminopsin (eLMO3) or a mutated form (R115A) that can generate bioluminescence but not excite neurons were injected into mouse sciatic nerves. After retrograde transport and viral transduction, nerves were cut and repaired by simple end-to-end anastomosis, and mice were treated with a single dose of CTZ. Results—Four weeks after nerve injury, compound muscle action potentials (M waves) recorded in response to sciatic nerve stimulation were more than fourfold larger in mice expressing the excitatory luminopsin than in controls expressing the mutant luminopsin. The number of motor and sensory neurons retrogradely labeled from reinnervated muscles in mice expressing eLMO3 was significantly greater than the number in mice expressing the R115A luminopsin and not significantly different from those in intact mice. When viral injection was delayed so that luminopsin expression was induced after nerve injury, a clinically relevant scenario, evoked M waves recorded from reinnervated muscles were significantly larger after injury in eLMO3-expressing mice. Conclusions—Treatment of peripheral nerve injuries using BL-OG has significant potential to enhance axon regeneration and promote functional recovery. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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Review

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54 pages, 15946 KiB

Open AccessReview

Brief Electrical Stimulation Promotes Recovery after Surgical Repair of Injured Peripheral Nerves

by Tessa Gordon

Int. J. Mol. Sci. 2024, 25(1), 665; https://doi.org/10.3390/ijms25010665 - 4 Jan 2024

Cited by 3 | Viewed by 2718

Abstract

Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. Yet, functional recovery after surgical repair is often disappointing. The basis for poor recovery is progressive deterioration with time and distance of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. Nonetheless, chronically denervated atrophic muscle retains the capacity for reinnervation. Declining electrical activity of motoneurons accompanies the progressive fall in axotomized neuronal and denervated SC expression of regeneration-associated-genes and declining regenerative success. Reduced motoneuronal activity is due to the withdrawal of synaptic contacts from the soma. Exogenous neurotrophic factors that promote nerve regeneration can replace the endogenous factors whose expression declines with time. But the profuse axonal outgrowth they provoke and the difficulties in their delivery hinder their efficacy. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) proximal to the injury site promotes the expression of endogenous growth factors and, in turn, dramatically accelerates axon outgrowth and target reinnervation. The latter ES effect has been demonstrated in both rats and humans. A conditioning ES of intact nerve days prior to nerve injury increases axonal outgrowth and regeneration rate. Thereby, this form of ES is amenable for nerve transfer surgeries and end-to-side neurorrhaphies. However, additional surgery for applying the required electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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20 pages, 6403 KiB

Open AccessReview

Inflammatory Mediators of Axon Regeneration in the Central and Peripheral Nervous Systems

by Larry I. Benowitz, Lili Xie and Yuqin Yin

Int. J. Mol. Sci. 2023, 24(20), 15359; https://doi.org/10.3390/ijms242015359 - 19 Oct 2023

Cited by 2 | Viewed by 2076

Abstract

Although most pathways in the mature central nervous system cannot regenerate when injured, research beginning in the late 20th century has led to discoveries that may help reverse this situation. Here, we highlight research in recent years from our laboratory identifying oncomodulin (Ocm), stromal cell-derived factor (SDF)-1, and chemokine CCL5 as growth factors expressed by cells of the innate immune system that promote axon regeneration in the injured optic nerve and elsewhere in the central and peripheral nervous systems. We also review the role of ArmC10, a newly discovered Ocm receptor, in mediating many of these effects, and the synergy between inflammation-derived growth factors and complementary strategies to promote regeneration, including deleting genes encoding cell-intrinsic suppressors of axon growth, manipulating transcription factors that suppress or promote the expression of growth-related genes, and manipulating cell-extrinsic suppressors of axon growth. In some cases, combinatorial strategies have led to unprecedented levels of nerve regeneration. The identification of some similar mechanisms in human neurons offers hope that key discoveries made in animal models may eventually lead to treatments to improve outcomes after neurological damage in patients. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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21 pages, 5040 KiB

Open AccessReview

The Dynamics of Nerve Degeneration and Regeneration in a Healthy Milieu and in Diabetes

by Lars B. Dahlin

Int. J. Mol. Sci. 2023, 24(20), 15241; https://doi.org/10.3390/ijms242015241 - 16 Oct 2023

Cited by 6 | Viewed by 2654

Abstract

Appropriate animal models, mimicking conditions of both health and disease, are needed to understand not only the biology and the physiology of neurons and other cells under normal conditions but also under stress conditions, like nerve injuries and neuropathy. In such conditions, understanding how genes and different factors are activated through the well-orchestrated programs in neurons and other related cells is crucial. Knowledge about key players associated with nerve regeneration intended for axonal outgrowth, migration of Schwann cells with respect to suitable substrates, invasion of macrophages, appropriate conditioning of extracellular matrix, activation of fibroblasts, formation of endothelial cells and blood vessels, and activation of other players in healthy and diabetic conditions is relevant. Appropriate physical and chemical attractions and repulsions are needed for an optimal and directed regeneration and are investigated in various nerve injury and repair/reconstruction models using healthy and diabetic rat models with relevant blood glucose levels. Understanding dynamic processes constantly occurring in neuropathies, like diabetic neuropathy, with concomitant degeneration and regeneration, requires advanced technology and bioinformatics for an integrated view of the behavior of different cell types based on genomics, transcriptomics, proteomics, and imaging at different visualization levels. Single-cell-transcriptional profile analysis of different cells may reveal any heterogeneity among key players in peripheral nerves in health and disease. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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10 pages, 875 KiB

Open AccessReview

Advancing Nerve Regeneration: Translational Perspectives of Tacrolimus (FK506)

by Simeon C. Daeschler, Konstantin Feinberg, Leila Harhaus, Ulrich Kneser, Tessa Gordon and Gregory H. Borschel

Int. J. Mol. Sci. 2023, 24(16), 12771; https://doi.org/10.3390/ijms241612771 - 14 Aug 2023

Cited by 10 | Viewed by 2364

Abstract

Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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16 pages, 4716 KiB

Open AccessReview

The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal

by Konstantin Feinberg, Kiana Tajdaran, Kaveh Mirmoeini, Simeon C. Daeschler, Mario A. Henriquez, Katelyn E. Stevens, Chilando M. Mulenga, Arif Hussain, Pedram Hamrah, Asim Ali, Tessa Gordon and Gregory H. Borschel

Int. J. Mol. Sci. 2023, 24(16), 12615; https://doi.org/10.3390/ijms241612615 - 9 Aug 2023

Cited by 8 | Viewed by 2672

Abstract

The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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34 pages, 5806 KiB

Open AccessReview

Trigeminal Sensory Supply Is Essential for Motor Recovery after Facial Nerve Injury

by Svenja Rink-Notzon, Jannika Reuscher, Klaus Nohroudi, Marilena Manthou, Tessa Gordon and Doychin N. Angelov

Int. J. Mol. Sci. 2022, 23(23), 15101; https://doi.org/10.3390/ijms232315101 - 1 Dec 2022

Cited by 6 | Viewed by 2550

Abstract

Recovery of mimic function after facial nerve transection is poor. The successful regrowth of regenerating motor nerve fibers to reinnervate their targets is compromised by (i) poor axonal navigation and excessive collateral branching, (ii) abnormal exchange of nerve impulses between adjacent regrowing axons, namely axonal crosstalk, and (iii) insufficient synaptic input to the axotomized facial motoneurons. As a result, axotomized motoneurons become hyperexcitable but unable to discharge. We review our findings, which have addressed the poor return of mimic function after facial nerve injuries, by testing the hypothesized detrimental component, and we propose that intensifying the trigeminal sensory input to axotomized and electrophysiologically silent facial motoneurons improves the specificity of the reinnervation of appropriate targets. We compared behavioral, functional, and morphological parameters after single reconstructive surgery of the facial nerve (or its buccal branch) with those obtained after identical facial nerve surgery, but combined with direct or indirect stimulation of the ipsilateral infraorbital nerve. We found that both methods of trigeminal sensory stimulation, i.e., stimulation of the vibrissal hairs and manual stimulation of the whisker pad, were beneficial for the outcome through improvement of the quality of target reinnervation and recovery of vibrissal motor performance. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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30 pages, 3365 KiB

Open AccessReview

Unleashing Intrinsic Growth Pathways in Regenerating Peripheral Neurons

by Trevor Poitras and Douglas W. Zochodne

Int. J. Mol. Sci. 2022, 23(21), 13566; https://doi.org/10.3390/ijms232113566 - 5 Nov 2022

Cited by 9 | Viewed by 2498

Abstract

Common mechanisms of peripheral axon regeneration are recruited following diverse forms of damage to peripheral nerve axons. Whether the injury is traumatic or disease related neuropathy, reconnection of axons to their targets is required to restore function. Supporting peripheral axon regrowth, while not yet available in clinics, might be accomplished from several directions focusing on one or more of the complex stages of regrowth. Direct axon support, with follow on participation of supporting Schwann cells is one approach, emphasized in this review. However alternative approaches might include direct support of Schwann cells that instruct axons to regrow, manipulation of the inflammatory milieu to prevent ongoing bystander axon damage, or use of inflammatory cytokines as growth factors. Axons may be supported by a growing list of growth factors, extending well beyond the classical neurotrophin family. The understanding of growth factor roles continues to expand but their impact experimentally and in humans has faced serious limitations. The downstream signaling pathways that impact neuron growth have been exploited less frequently in regeneration models and rarely in human work, despite their promise and potency. Here we review the major regenerative signaling cascades that are known to influence adult peripheral axon regeneration. Within these pathways there are major checkpoints or roadblocks that normally check unwanted growth, but are an impediment to robust growth after injury. Several molecular roadblocks, overlapping with tumour suppressor systems in oncology, operate at the level of the perikarya. They have impacts on overall neuron plasticity and growth. A second approach targets proteins that largely operate at growth cones. Addressing both sites might offer synergistic benefits to regrowing neurons. This review emphasizes intrinsic aspects of adult peripheral axon regeneration, emphasizing several molecular barriers to regrowth that have been studied in our laboratory. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury)

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