Peripheral Nerve Plasticity: Development and Regeneration

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: closed (25 August 2022) | Viewed by 13568

Special Issue Editors

Department of Anatomy, College of Graduate Studies and Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA
Interests: plasticity of the peripheral nervous system; nerve regeneration; adulthood and development
Department of Clinical and Biological Sciences, and Cavalieri Ottolenghi Neuroscience Institute, University of Turin, Ospedale San Luigi, Regione Gonzole 10, 10043 Orbassano, Turin, Italy
Interests: peripheral nervous system; nerve repair; schwann cells; axon growth; demyelination and remyelination; neurotrophic factors; neuregulin; neuroimmunomodulation; photomodulation
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Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to a Special Issue dedicated to the peripheral nervous system that aims to highlight its plasticity during development and adulthood. The peripheral nervous system originates from neural precursors of the neural crest that differentiate into a variety of different cell types that are able to guide the fibers to the periphery to establish precise contact with a target. This sophisticated system is able to conduct sensory inputs and convey motor outputs while still maintaining its regenerating capability throughout life to sustain possible mechanical injury and activate repair mechanisms.

Prof. Dr. Michele Fornaro
Prof. Dr. Stefano Geuna
Guest Editors

Manuscript Submission Information

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Keywords

  • neural crest;
  • neural progenitors;
  • environmental cues;
  • axonal growth;
  • axonal cone;
  • neurotropic factors;
  • semaphorin;
  • nerve insult;
  • neuroma;
  • axonal guidance;
  • biomaterial and scaffolding.

Published Papers (4 papers)

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Research

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18 pages, 4089 KiB  
Article
Functional Gait Assessment Using Manual, Semi-Automated and Deep Learning Approaches Following Standardized Models of Peripheral Nerve Injury in Mice
by Daniel Umansky, Kathleen M. Hagen, Tak Ho Chu, Rajesh K. Pathiyil, Saud Alzahrani, Shalina S. Ousman and Rajiv Midha
Biomolecules 2022, 12(10), 1355; https://doi.org/10.3390/biom12101355 - 23 Sep 2022
Cited by 4 | Viewed by 1849
Abstract
Objective: To develop a standardized model of stretch–crush sciatic nerve injury in mice, and to compare outcomes of crush and novel stretch–crush injuries using standard manual gait and sensory assays, and compare them to both semi-automated as well as deep-learning gait analysis methods. [...] Read more.
Objective: To develop a standardized model of stretch–crush sciatic nerve injury in mice, and to compare outcomes of crush and novel stretch–crush injuries using standard manual gait and sensory assays, and compare them to both semi-automated as well as deep-learning gait analysis methods. Methods: Initial studies in C57/Bl6 mice were used to develop crush and stretch–crush injury models followed by histologic analysis. In total, 12 eight-week-old 129S6/SvEvTac mice were used in a six-week behavioural study. Behavioral assessments using the von Frey monofilament test and gait analysis recorded on a DigiGait platform and analyzed through both Visual Gait Lab (VGL) deep learning and standardized sciatic functional index (SFI) measurements were evaluated weekly. At the termination of the study, neurophysiological nerve conduction velocities were recorded, calf muscle weight ratios measured and histological analyses performed. Results: Histological evidence confirmed more severe histomorphological injury in the stretch–crush injured group compared to the crush-only injured group at one week post-injury. Von Frey monofilament paw withdrawal was significant for both groups at week one compared to baseline (p < 0.05), but not between groups with return to baseline at week five. SFI showed hindered gait at week one and two for both groups, compared to baseline (p < 0.0001), with return to baseline at week five. Hind stance width (HSW) showed similar trends as von Frey monofilament test as well as SFI measurements, yet hind paw angle (HPA) peaked at week two. Nerve conduction velocity (NCV), measured six weeks post-injury, at the termination of the study, did not show any significant difference between the two groups; yet, calf muscle weight measurements were significantly different between the two, with the stretch–crush group demonstrating a lower (poorer) weight ratio relative to uninjured contralateral legs (p < 0.05). Conclusion: Stretch–crush injury achieved a more reproducible and constant injury compared to crush-only injuries, with at least a Sunderland grade 3 injury (perineurial interruption) in histological samples one week post-injury in the former. However, serial behavioral outcomes were comparable between the two crush groups, with similar kinetics of recovery by von Frey testing, SFI and certain VGL parameters, the latter reported for the first time in rodent peripheral nerve injury. Semi-automated and deep learning-based approaches for gait analysis are promising, but require further validation for evaluation in murine hind-limb nerve injuries. Full article
(This article belongs to the Special Issue Peripheral Nerve Plasticity: Development and Regeneration)
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19 pages, 5503 KiB  
Article
Submicron Topographically Patterned 3D Substrates Enhance Directional Axon Outgrowth of Dorsal Root Ganglia Cultured Ex Vivo
by Michele Fornaro, Christopher Dipollina, Darryl Giambalvo, Robert Garcia, Casey Sigerson, Harsh Sharthiya, Claire Liu, Paul F. Nealey, Kolbrun Kristjansdottir and Joshua Z. Gasiorowski
Biomolecules 2022, 12(8), 1059; https://doi.org/10.3390/biom12081059 - 30 Jul 2022
Cited by 1 | Viewed by 1754
Abstract
A peripheral nerve injury results in disruption of the fiber that usually protects axons from the surrounding environment. Severed axons from the proximal nerve stump are capable of regenerating, but axons are exposed to a completely new environment. Regeneration recruits cells that produce [...] Read more.
A peripheral nerve injury results in disruption of the fiber that usually protects axons from the surrounding environment. Severed axons from the proximal nerve stump are capable of regenerating, but axons are exposed to a completely new environment. Regeneration recruits cells that produce and deposit key molecules, including growth factor proteins and fibrils in the extracellular matrix (ECM), thus changing the chemical and geometrical environment. The regenerating axons thus surf on a newly remodeled micro-landscape. Strategies to enhance and control axonal regeneration and growth after injury often involve mimicking the extrinsic cues that are found in the natural nerve environment. Indeed, nano- and micropatterned substrates have been generated as tools to guide axons along a defined path. The mechanical cues of the substrate are used as guides to orient growth or change the direction of growth in response to impediments or cell surface topography. However, exactly how axons respond to biophysical information and the dynamics of axonal movement are still poorly understood. Here we use anisotropic, groove-patterned substrate topography to direct and enhance sensory axonal growth of whole mouse dorsal root ganglia (DRG) transplanted ex vivo. Our results show significantly enhanced and directed growth of the DRG sensory fibers on the hemi-3D topographic substrates compared to a 0 nm pitch, flat control surface. By assessing the dynamics of axonal movement in time-lapse microscopy, we found that the enhancement was not due to increases in the speed of axonal growth, but to the efficiency of growth direction, ensuring axons minimize movement in undesired directions. Finally, the directionality of growth was reproduced on topographic patterns fabricated as fully 3D substrates, potentially opening new translational avenues of development incorporating these specific topographic feature sizes in implantable conduits in vivo. Full article
(This article belongs to the Special Issue Peripheral Nerve Plasticity: Development and Regeneration)
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30 pages, 6696 KiB  
Article
Effects of Olfactory Mucosa Stem/Stromal Cell and Olfactory Ensheating Cells Secretome on Peripheral Nerve Regeneration
by Rui D. Alvites, Mariana V. Branquinho, Ana C. Sousa, Bruna Lopes, Patrícia Sousa, Justina Prada, Isabel Pires, Giulia Ronchi, Stefania Raimondo, Ana L. Luís, Stefano Geuna, Artur Severo P. Varejão and Ana Colette Maurício
Biomolecules 2022, 12(6), 818; https://doi.org/10.3390/biom12060818 - 11 Jun 2022
Cited by 2 | Viewed by 2145
Abstract
Cell secretome has been explored as a cell-free technique with high scientific and medical interest for Regenerative Medicine. In this work, the secretome produced and collected from Olfactory Mucosa Mesenchymal Stem Cells and Olfactory Ensheating Cells was analyzed and therapeutically applied to promote [...] Read more.
Cell secretome has been explored as a cell-free technique with high scientific and medical interest for Regenerative Medicine. In this work, the secretome produced and collected from Olfactory Mucosa Mesenchymal Stem Cells and Olfactory Ensheating Cells was analyzed and therapeutically applied to promote peripheral nerve regeneration. The analysis of the conditioned medium revealed the production and secretion of several factors with immunomodulatory functions, capable of intervening beneficially in the phases of nerve regeneration. Subsequently, the conditioned medium was applied to sciatic nerves of rats after neurotmesis, using Reaxon® as tube-guides. Over 20 weeks, the animals were subjected to periodic functional assessments, and after this period, the sciatic nerves and cranial tibial muscles were evaluated stereologically and histomorphometrically, respectively. The results obtained allowed to confirm the beneficial effects resulting from the application of this therapeutic combination. The administration of conditioned medium from Olfactory Mucosal Mesenchymal Stem Cells led to the best results in motor performance, sensory recovery, and gait patterns. Stereological and histomorphometric evaluation also revealed the ability of this therapeutic combination to promote nervous and muscular histologic reorganization during the regenerative process. The therapeutic combination discussed in this work shows promising results and should be further explored to clarify irregularities found in the outcomes and to allow establishing the use of cell secretome as a new therapeutic field applied in the treatment of peripheral nerves after injury. Full article
(This article belongs to the Special Issue Peripheral Nerve Plasticity: Development and Regeneration)
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Review

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18 pages, 1489 KiB  
Review
The Effect of Electrical Stimulation on Nerve Regeneration Following Peripheral Nerve Injury
by Luke Juckett, Tiam Mana Saffari, Benjamin Ormseth, Jenna-Lynn Senger and Amy M. Moore
Biomolecules 2022, 12(12), 1856; https://doi.org/10.3390/biom12121856 - 12 Dec 2022
Cited by 17 | Viewed by 7255
Abstract
Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from [...] Read more.
Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from chronic pain, and sensory and motor dysfunction. One promising surgical adjunct is the application of intraoperative electrical stimulation (ES) to peripheral nerves. ES acts through second messenger cyclic AMP to augment the intrinsic molecular pathways of regeneration. Decades of animal studies have demonstrated that 20 Hz ES delivered post-surgically accelerates axonal outgrowth and end organ reinnervation. This work has been translated clinically in a series of randomized clinical trials, which suggest that ES can be used as an efficacious therapy to improve patient outcomes following PNIs. The aim of this review is to discuss the cellular physiology and the limitations of regeneration after peripheral nerve injuries. The proposed mechanisms of ES protocols and how they facilitate nerve regeneration depending on timing of administration are outlined. Finally, future directions of research that may provide new perspectives on the optimal delivery of ES following PNI are discussed. Full article
(This article belongs to the Special Issue Peripheral Nerve Plasticity: Development and Regeneration)
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