EDITORIAL published: 15 October 2019 doi: 10.3389/fncel.2019.00464 Editorial: Peripheral Nerve Regeneration Giovanna Gambarotta 1 , Stefania Raimondo 1,2 , Esther Udina 3 , James B. Phillips 4,5 and Kirsten Haastert-Talini 6,7* 1 Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy, 2 Neuroscience Institute of the “Cavalieri Ottolenghi” Foundation (NICO), University of Torino, Orbassano, Italy, 3 Department of Cell Biology, Physiology and Immunology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain, 4 Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom, 5 UCL Centre for Nerve Engineering, University College London, London, United Kingdom, 6 Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hanover, Germany, 7 Center for Systems Neuroscience (ZSN) Hannover, Hanover, Germany Keywords: axotomy, nerve guide, nerve graft, nerve sheath tumor, Schwann cells, dorsal root ganglion neurons, motoneurons, functional recovery Editorial on the Research Topic Peripheral Nerve Regeneration The Research Topic entitled “Peripheral Nerve Regeneration” is focused on strategies to promote and improve the same. Injuries to peripheral nerves have variable causation such as metabolic or hereditary poly-neuropathies, nerve sheath tumors, or nerve trauma resulting from occupational or car accidents or combat activities. Although knowledge on the processes allowing peripheral nerve regeneration after degeneration or injury has been significantly increased over the last decades, and although (micro-)surgical methods have been refined considerably, more research is still needed to minimize consequences for patients and society. Treatment of acutely or chronically injured peripheral nerves is far from being optimal. Patients suffer from severe impairment of Edited and reviewed by: Arianna Maffei, their quality of life due to continuous disabilities and their treatment is still affiliated with high Stony Brook University, United States socio-economic costs. We are very grateful to the 123 authors from 14 different countries and five continents that *Correspondence: Kirsten Haastert-Talini contributed to the current Research Topic with seven review articles and 12 original research Haastert-Talini.Kirsten@ articles. These publications look from different angles into the current challenges for the field. For mh-hannover.de more than 100 years investigative surgeons and basic researchers have revealed solid knowledge on (1) key events orchestrating the process of peripheral nerve regeneration, and (2) basic mechanisms Specialty section: and pathways that need to be activated or blocked for axonal regeneration and correct reinnervation This article was submitted to of peripheral target tissue. They have also discovered (3) cellular key players and how lineage Cellular Neurophysiology, reprogramming is generating them, and, not to forget, (4) surgical approaches and biomaterials a section of the journal supporting successful recovery. Frontiers in Cellular Neuroscience This collection of articles adds insights to the aforementioned knowledge and also provides Received: 24 September 2019 technical information worth considering in future research. In the following we first give Accepted: 30 September 2019 an overview about the included review articles before shortly reporting on the original Published: 15 October 2019 research articles. Citation: Ronchi et al. analyzed the potential applications, advantages and limitations of the rat median Gambarotta G, Raimondo S, Udina E, nerve injury and repair model in pre-clinical research. They provide a synthetic overview of a Phillips JB and Haastert-Talini K (2019) Editorial: Peripheral Nerve variety of methods that can be applied in this model for assessing functional nerve regeneration Regeneration. and present informative tables about the research that has made use of this model. Also the Front. Cell. Neurosci. 13:464. article of Lovati et al. considers pre-clinical work performed in rat models. They performed a doi: 10.3389/fncel.2019.00464 systematic review of the literature (from January 2007 to October 2017) regarding the different Frontiers in Cellular Neuroscience | www.frontiersin.org 1 October 2019 | Volume 13 | Article 464 Gambarotta et al. Editorial: Peripheral Nerve Regeneration decellularization protocols used and aimed, through assessment as the gold standard to repair especially long nerve defects. of the results from histological and functional read-outs, to The paper of Wilcox et al. considers a technical issue for going compare the effectiveness of the different nerve grafts. Boecker beyond rodent models in peripheral nerve research. For ethical et al. reviewed the clinical relevance of chitosan derived nerve and practical reasons, research of nerve injury and repair is guides for short gap repair in human patients. They give an focused to rodent models. Nevertheless, during reconstructive overview on the physiologic properties of chitosan in comparison nerve repair it is sometimes possible to obtain human nerve to other nerve guide materials and discuss actual and future samples. These samples are, however, exposed to the complex translation of chitosan into clinical practice. surgical environment, bringing them in contact with chemical In their article Duraikannu et al. review the regenerative and physical factors which are not present when sampling animal capacity of adult neurons and novel intrinsic pathways that tissues in a research laboratory. With the aim of optimizing have impact on axonal regrowth, downstream from growth protocols for the efficient extraction of RNA for quantitative factor receptors. They thereby describe a novel approach analysis, the authors characterized the effect of time delays before to enhance the intrinsic growth of adult neurons, targeting cryopreservation and the effect of contact with antiseptic surgical neuronal inhibitors of regeneration, like tumor suppressor reagents on the quantity and quality of RNA isolated from human molecules, by means of non-viral siRNA. Orchestration of samples in comparison to rat nerve samples. proteases and secretases during Wallerian degeneration and The efficacy of two novel bioartificial nerve grafts has been setting-up of a pro-regenerative environment is the focus of the investigated by other groups in two different models, the 10 mm article contributed by Pellegatta and Taveggia. They describe rat median nerve and the 10 mm rat sciatic nerve model. the role of different proteases and secretases in controlling, Dietzmeyer et al. report their analysis of a more bendable 2- on a post-translational level, the activity of transmembrane chambered chitosan nerve guide. Bendability was increased by proteins involved in peripheral nerve regeneration, among which a corrugated outer wall and the chambers were formed by the neurotrophin receptor p75NTR , the receptor Notch, the longitudinally introducing a perforated chitosan film to assist growth factor Neuregulin-1, and how this creates a permissive axonal outgrowth. The authors evaluated functional regeneration environment to allow successful regeneration of injured axons. with three methods in the advanced rat median nerve model Jessen and Mirsky review the remarkable plasticity of Schwann and demonstrate that the device represents a promising and cells and the characteristics of the denervated repair Schwann innovative alternative for nerve repair in mobile body parts cell population. Knowledge about their distinct properties such as digits. Chato-Astrain et al. describe their attempt to and cell-type specific control mechanisms can potentially be produce a tissue engineered nerve graft from mesenchymal used to foster the development of effective treatments, further stem cells integrated into a nanostructured hydrogel. They increasing regenerative potential and maintaining repair capacity evaluated their graft alone or introduced into clinically approved for the extended periods that are required for substantial collagen type I nerve guides in the rat sciatic nerve model. nerve regeneration. The results presented suggest that the novel nanostructured Neurotrophic factors and especially brain derived fibrin-agarose bio-artificial nerve substitutes support nerve tissue neurotrophic factor (BDNF) are known to modulate axonal regeneration and functional recovery to an extent similar to the regeneration. McGregor and English put a particular focus on autograft control. discussing the role of BDNF in activity-dependent treatments to As also discussed in the review by McGregor and English, enhance regeneration such as electrical stimulation, exercise, and already mentioned above, physical exercise has been shown to optogenetic stimulation. The authors further discuss the impact add positive effects on motor recovery after nerve transection of a common single nucleotide polymorphism in the human and repair. In this context Arbat-Plana et al. investigated how bdfn gene, Val66Met, on the effectiveness of these treatments and physical exercise can modulate the synaptic stripping and other emphasize the need for personalized regenerative medicine. spinal changes that spinal motoneurons undergo after axotomy The original research articles included into this Research in a rat model of end-to-end sciatic nerve repair. They describe Topic, again, cover versatile aspects of peripheral nerve that in addition to the activity-dependent modulation of the regeneration research. BDNF system, noradrenergic projections of the locus coerules The characteristic properties of the graft material will have an are important for some but not all the effects that exercise important impact on the outcome of functional recovery after induces on the spinal cord after peripheral nerve injury. Besides nerve gap repair. This is not only true for bioartificial grafts, but physical exercise, also supplementation of specific nutrients is also for autografts that are commonly harvested from sensory frequently discussed to support peripheral nerve regeneration. nerves and implanted into motor (mixed) nerves. In this context The paper of Li et al. investigated the effects of ascorbic acid Hercher et al. evaluated regeneration-associated gene expression (vitamin C), an essential micronutrient, on nerve regeneration in homotopic or heterotopic 6 mm rat femoral nerve grafts. They in vivo in mice and in vitro. The study showed that ascorbic describe evident spatiotemporal differences in the expression of acid improved regeneration and functional recovery following some trophic factors and cell adhesion molecules between grafts sciatic nerve crush, promoted neurite outgrowth in dorsal from sensory and motor branches. Although differences in the root ganglion (DRG) neuron cultures, enhanced proliferation capabilities of these grafts to sustain motor regeneration in their and migration behavior in primary Schwann cell cultures, and short gap repair model were minor, the paper contributes to positively modulated the polarization of primary macrophages in the debate about the concerns of using sensory donor nerves culture toward the pro-regenerative phenotype. Frontiers in Cellular Neuroscience | www.frontiersin.org 2 October 2019 | Volume 13 | Article 464 Gambarotta et al. Editorial: Peripheral Nerve Regeneration Since sufficient peripheral nerve regeneration obviously chronic denervation of either 7 weeks or 17 months, showing in depends on axonal outgrowth and its support by Schwann cells, vitro that these cells retained their capacity to myelinate DRG we have included into this special issue also basic research papers neurites, although with a reduced capacity. They hypothesized reporting novel knowledge about these topics. The critical role that, although these Schwann cells retain their ability to respond of micro domains in cell membranes, specifically cholesterol-rich to axonal signals and to elaborate myelin, their low numbers lipid rafts which cluster proteins and other molecules together, and their reduced capacity to proliferate might account, at least is explored by Roselló-Busquets et al. using a series of in vitro in part, for the poor functional recovery observed after delayed and mouse in vivo models. This study showed that cholesterol surgical repair of injured peripheral nerves. depletion disrupted lipid rafts, altered growth cone morphology, The last, but not least, publication included into this Research and resulted in increased axonal growth during development and Topic, is a contribution of Stratton et al. who elucidated the after axotomy, with implications for both peripheral and central role of the microenvironment to sustain/suppress malignant nervous system research. peripheral nerve sheath tumors (MPNST) that usually lead It is widely accepted that the neurotrophin receptor p75NTR to aggressive nerve resections. Therefore, strategies aimed to is a central component in nerve regeneration, but since it is suppress proliferation of these tumors would limit the functional expressed in both neurons and glia and has been associated with loss derived from these malignancies. The authors present a a wide range of cellular behaviors its specific role remains elusive. novel in vitro model for studying MPNST by using isolated adult Gonçalves et al. generated a conditional knockout mouse model rodent Schwann cells and their results strengthen the finding to silence expression of p75NTR specifically in Schwann cells, that balanced properties of the tissue environment are crucial for subsequently showing that Schwann cell p75NTR is not critical tumor-suppression and point out to the high importance of the for axonal regrowth or remyelination following crush injury, endoneurial tissue in this context. although its absence did reduce nerve conduction velocity. We, the guest editors, thank all authors one more time for their Following injury, the axons and their terminals release valuable contributions and hope that the readers of this Research mitochondrial DNA (mtDNA) fragments and proteins known Topic will, as much as we did, enjoy learning the expert opinions as “mitochondrial damage-associated molecular patterns” and excellent research results presented. (mtDAMPs). In their paper, Korimová et al. hypothesized that mtDAMPs might stimulate Schwann cells to put out cytoplasmic AUTHOR CONTRIBUTIONS processes through the action of the corresponding receptors and tested their hypothesis in vitro in RT4-D6P2T schwannoma cells. All the authors have contributed to this editorial, writing Schwann cell proliferation is an important component of the comments to the different articles. KH-T has connected them all peripheral nerve injury response and Tan et al. explored the within the Editorial. effect of inhibiting RhoA-subfamily GTPases with C3 transferase on this process, since RhoA inhibition is an established target Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a used for improving neural regeneration. Using an in vitro potential conflict of interest. model they showed that the C3 transferase CT04 suppressed primary Schwann cell proliferation, but that this was likely to Copyright © 2019 Gambarotta, Raimondo, Udina, Phillips and Haastert-Talini. be independent of the ROCK pathway and instead involved This is an open-access article distributed under the terms of the Creative Commons inactivation of the AKT pathway. Also related to the topic Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited of Schwann cell proliferation, Gordon et al. analyzed the and that the original publication in this journal is cited, in accordance with accepted proliferative capacity of rat Schwann cells obtained from distal academic practice. No use, distribution or reproduction is permitted which does not nerve stumps subjected to acute denervation of 7 days or comply with these terms. Frontiers in Cellular Neuroscience | www.frontiersin.org 3 October 2019 | Volume 13 | Article 464