Gambarotta, G.

Haastert-Talini, K.

Phillips, J. B.

Raimondo, S.

Udina, E.

English

Institutional Research Information System University of Turin

EDITORIALpublished: 15 October 2019doi: 10.3389/fncel.2019.00464Frontiers in Cellular Neuroscience | www.frontiersin.org 1 October 2019 | Volume 13 | Article 464Edited and reviewed by:Arianna Maffei,Stony Brook University, United States*Correspondence:Kirsten Haastert-TaliniHaastert-Talini.Kirsten@mh-hannover.deSpecialty section:This article was submitted toCellular Neurophysiology,a section of the journalFrontiers in Cellular NeuroscienceReceived: 24 September 2019Accepted: 30 September 2019Published: 15 October 2019Citation:Gambarotta G, Raimondo S, Udina E,Phillips JB and Haastert-Talini K(2019) Editorial: Peripheral NerveRegeneration.Front. Cell. Neurosci. 13:464.doi: 10.3389/fncel.2019.00464Editorial: Peripheral NerveRegenerationGiovanna Gambarotta 1, Stefania Raimondo 1,2, Esther Udina 3, James B. Phillips 4,5 andKirsten Haastert-Talini 6,7*1Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy, 2Neuroscience Institute of the“Cavalieri Ottolenghi” Foundation (NICO), University of Torino, Orbassano, Italy, 3Department of Cell Biology, Physiology andImmunology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Institute ofNeurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain, 4Department of Pharmacology, UCL School ofPharmacy, University College London, London, United Kingdom, 5UCL Centre for Nerve Engineering, University CollegeLondon, London, United Kingdom, 6 Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hanover,Germany, 7Center for Systems Neuroscience (ZSN) Hannover, Hanover, GermanyKeywords: axotomy, nerve guide, nerve graft, nerve sheath tumor, Schwann cells, dorsal root ganglion neurons,motoneurons, functional recoveryEditorial on the Research TopicPeripheral Nerve RegenerationThe Research Topic entitled “Peripheral Nerve Regeneration” is focused on strategies to promoteand improve the same. Injuries to peripheral nerves have variable causation such as metabolic orhereditary poly-neuropathies, nerve sheath tumors, or nerve trauma resulting from occupational orcar accidents or combat activities. Although knowledge on the processes allowing peripheral nerveregeneration after degeneration or injury has been significantly increased over the last decades,and although (micro-)surgical methods have been refined considerably, more research is stillneeded to minimize consequences for patients and society. Treatment of acutely or chronicallyinjured peripheral nerves is far from being optimal. Patients suffer from severe impairment oftheir quality of life due to continuous disabilities and their treatment is still affiliated with highsocio-economic costs.We are very grateful to the 123 authors from 14 different countries and five continents thatcontributed to the current Research Topic with seven review articles and 12 original researcharticles. These publications look from different angles into the current challenges for the field. Formore 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 mechanismsand pathways that need to be activated or blocked for axonal regeneration and correct reinnervationof peripheral target tissue. They have also discovered (3) cellular key players and how lineagereprogramming is generating them, and, not to forget, (4) surgical approaches and biomaterialssupporting successful recovery.This collection of articles adds insights to the aforementioned knowledge and also providestechnical information worth considering in future research. In the following we first givean overview about the included review articles before shortly reporting on the originalresearch articles.Ronchi et al. analyzed the potential applications, advantages and limitations of the rat mediannerve injury and repair model in pre-clinical research. They provide a synthetic overview of avariety of methods that can be applied in this model for assessing functional nerve regenerationand present informative tables about the research that has made use of this model. Also thearticle of Lovati et al. considers pre-clinical work performed in rat models. They performed asystematic review of the literature (from January 2007 to October 2017) regarding the differentGambarotta et al. Editorial: Peripheral Nerve Regenerationdecellularization protocols used and aimed, through assessmentof the results from histological and functional read-outs, tocompare the effectiveness of the different nerve grafts. Boeckeret al. reviewed the clinical relevance of chitosan derived nerveguides for short gap repair in human patients. They give anoverview on the physiologic properties of chitosan in comparisonto other nerve guide materials and discuss actual and futuretranslation of chitosan into clinical practice.In their article Duraikannu et al. review the regenerativecapacity of adult neurons and novel intrinsic pathways thathave impact on axonal regrowth, downstream from growthfactor receptors. They thereby describe a novel approachto enhance the intrinsic growth of adult neurons, targetingneuronal inhibitors of regeneration, like tumor suppressormolecules, by means of non-viral siRNA. Orchestration ofproteases and secretases during Wallerian degeneration andsetting-up of a pro-regenerative environment is the focus of thearticle contributed by Pellegatta and Taveggia. They describethe role of different proteases and secretases in controlling,on a post-translational level, the activity of transmembraneproteins involved in peripheral nerve regeneration, among whichthe neurotrophin receptor p75NTR, the receptor Notch, thegrowth factor Neuregulin-1, and how this creates a permissiveenvironment to allow successful regeneration of injured axons.Jessen and Mirsky review the remarkable plasticity of Schwanncells and the characteristics of the denervated repair Schwanncell population. Knowledge about their distinct propertiesand cell-type specific control mechanisms can potentially beused to foster the development of effective treatments, furtherincreasing regenerative potential andmaintaining repair capacityfor the extended periods that are required for substantialnerve regeneration.Neurotrophic factors and especially brain derivedneurotrophic factor (BDNF) are known to modulate axonalregeneration. McGregor and English put a particular focus ondiscussing the role of BDNF in activity-dependent treatments toenhance regeneration such as electrical stimulation, exercise, andoptogenetic stimulation. The authors further discuss the impactof a common single nucleotide polymorphism in the humanbdfn gene, Val66Met, on the effectiveness of these treatments andemphasize the need for personalized regenerative medicine.The original research articles included into this ResearchTopic, again, cover versatile aspects of peripheral nerveregeneration research.The characteristic properties of the graft material will have animportant impact on the outcome of functional recovery afternerve gap repair. This is not only true for bioartificial grafts, butalso for autografts that are commonly harvested from sensorynerves and implanted into motor (mixed) nerves. In this contextHercher et al. evaluated regeneration-associated gene expressionin homotopic or heterotopic 6mm rat femoral nerve grafts. Theydescribe evident spatiotemporal differences in the expression ofsome trophic factors and cell adhesion molecules between graftsfrom sensory and motor branches. Although differences in thecapabilities of these grafts to sustain motor regeneration in theirshort gap repair model were minor, the paper contributes tothe debate about the concerns of using sensory donor nervesas the gold standard to repair especially long nerve defects.The paper of Wilcox et al. considers a technical issue for goingbeyond rodent models in peripheral nerve research. For ethicaland practical reasons, research of nerve injury and repair isfocused to rodent models. Nevertheless, during reconstructivenerve repair it is sometimes possible to obtain human nervesamples. These samples are, however, exposed to the complexsurgical environment, bringing them in contact with chemicaland physical factors which are not present when sampling animaltissues in a research laboratory. With the aim of optimizingprotocols for the efficient extraction of RNA for quantitativeanalysis, the authors characterized the effect of time delays beforecryopreservation and the effect of contact with antiseptic surgicalreagents on the quantity and quality of RNA isolated from humansamples in comparison to rat nerve samples.The efficacy of two novel bioartificial nerve grafts has beeninvestigated by other groups in two different models, the 10mmrat median nerve and the 10mm rat sciatic nerve model.Dietzmeyer et al. report their analysis of a more bendable 2-chambered chitosan nerve guide. Bendability was increased bya corrugated outer wall and the chambers were formed bylongitudinally introducing a perforated chitosan film to assistaxonal outgrowth. The authors evaluated functional regenerationwith three methods in the advanced rat median nerve modeland demonstrate that the device represents a promising andinnovative alternative for nerve repair in mobile body partssuch as digits. Chato-Astrain et al. describe their attempt toproduce a tissue engineered nerve graft from mesenchymalstem cells integrated into a nanostructured hydrogel. Theyevaluated their graft alone or introduced into clinically approvedcollagen type I nerve guides in the rat sciatic nerve model.The results presented suggest that the novel nanostructuredfibrin-agarose bio-artificial nerve substitutes support nerve tissueregeneration and functional recovery to an extent similar to theautograft control.As also discussed in the review by McGregor and English,already mentioned above, physical exercise has been shown toadd positive effects on motor recovery after nerve transectionand repair. In this context Arbat-Plana et al. investigated howphysical exercise can modulate the synaptic stripping and otherspinal changes that spinal motoneurons undergo after axotomyin a rat model of end-to-end sciatic nerve repair. They describethat in addition to the activity-dependent modulation of theBDNF system, noradrenergic projections of the locus coerulesare important for some but not all the effects that exerciseinduces on the spinal cord after peripheral nerve injury. Besidesphysical exercise, also supplementation of specific nutrients isfrequently discussed to support peripheral nerve regeneration.The paper of Li et al. investigated the effects of ascorbic acid(vitamin C), an essential micronutrient, on nerve regenerationin vivo in mice and in vitro. The study showed that ascorbicacid improved regeneration and functional recovery followingsciatic nerve crush, promoted neurite outgrowth in dorsalroot ganglion (DRG) neuron cultures, enhanced proliferationand migration behavior in primary Schwann cell cultures, andpositively modulated the polarization of primary macrophages inculture toward the pro-regenerative phenotype.Frontiers in Cellular Neuroscience | www.frontiersin.org 2 October 2019 | Volume 13 | Article 464Gambarotta et al. Editorial: Peripheral Nerve RegenerationSince sufficient peripheral nerve regeneration obviouslydepends on axonal outgrowth and its support by Schwann cells,we have included into this special issue also basic research papersreporting novel knowledge about these topics. The critical roleof micro domains in cell membranes, specifically cholesterol-richlipid rafts which cluster proteins and other molecules together,is explored by Roselló-Busquets et al. using a series of in vitroand mouse in vivo models. This study showed that cholesteroldepletion disrupted lipid rafts, altered growth cone morphology,and resulted in increased axonal growth during development andafter axotomy, with implications for both peripheral and centralnervous system research.It is widely accepted that the neurotrophin receptor p75NTRis a central component in nerve regeneration, but since it isexpressed in both neurons and glia and has been associated witha wide range of cellular behaviors its specific role remains elusive.Gonçalves et al. generated a conditional knockout mouse modelto silence expression of p75NTR specifically in Schwann cells,subsequently showing that Schwann cell p75NTR is not criticalfor axonal regrowth or remyelination following crush injury,although its absence did reduce nerve conduction velocity.Following injury, the axons and their terminals releasemitochondrial DNA (mtDNA) fragments and proteins knownas “mitochondrial damage-associated molecular patterns”(mtDAMPs). In their paper, Korimová et al. hypothesized thatmtDAMPs might stimulate Schwann cells to put out cytoplasmicprocesses through the action of the corresponding receptors andtested their hypothesis in vitro in RT4-D6P2T schwannoma cells.Schwann cell proliferation is an important component of theperipheral nerve injury response and Tan et al. explored theeffect of inhibiting RhoA-subfamily GTPases with C3 transferaseon this process, since RhoA inhibition is an established targetused for improving neural regeneration. Using an in vitromodel they showed that the C3 transferase CT04 suppressedprimary Schwann cell proliferation, but that this was likely tobe independent of the ROCK pathway and instead involvedinactivation of the AKT pathway. Also related to the topicof Schwann cell proliferation, Gordon et al. analyzed theproliferative capacity of rat Schwann cells obtained from distalnerve stumps subjected to acute denervation of 7 days orchronic denervation of either 7 weeks or 17 months, showing invitro that these cells retained their capacity to myelinate DRGneurites, although with a reduced capacity. They hypothesizedthat, although these Schwann cells retain their ability to respondto axonal signals and to elaborate myelin, their low numbersand their reduced capacity to proliferate might account, at leastin part, for the poor functional recovery observed after delayedsurgical repair of injured peripheral nerves.The last, but not least, publication included into this ResearchTopic, is a contribution of Stratton et al. who elucidated therole of the microenvironment to sustain/suppress malignantperipheral nerve sheath tumors (MPNST) that usually leadto aggressive nerve resections. Therefore, strategies aimed tosuppress proliferation of these tumors would limit the functionalloss derived from these malignancies. The authors present anovel in vitromodel for studying MPNST by using isolated adultrodent Schwann cells and their results strengthen the findingthat balanced properties of the tissue environment are crucial fortumor-suppression and point out to the high importance of theendoneurial tissue in this context.We, the guest editors, thank all authors onemore time for theirvaluable contributions and hope that the readers of this ResearchTopic will, as much as we did, enjoy learning the expert opinionsand excellent research results presented.AUTHOR CONTRIBUTIONSAll the authors have contributed to this editorial, writingcomments to the different articles. KH-T has connected them allwithin the Editorial.Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2019 Gambarotta, Raimondo, Udina, Phillips and Haastert-Talini.This is an open-access article distributed under the terms of the Creative CommonsAttribution License (CC BY). The use, distribution or reproduction in other forumsis permitted, provided the original author(s) and the copyright owner(s) are creditedand that the original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction is permitted which does notcomply with these terms.Frontiers in Cellular Neuroscience | www.frontiersin.org 3 October 2019 | Volume 13 | Article 464

Editorial: Peripheral Nerve Regeneration

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Editorial: Peripheral Nerve Regeneration

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