Special Issue "Schwann Cells: From Formation to Clinical Significance"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 November 2020).

Special Issue Editor

Prof. Dr. Stefano Geuna
E-Mail Website
Guest Editor
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,

I am pleased to announce an upcoming Special Issue of Cells entitled “Schwann Cells: From Formation to Clinical Significance”. This Special Issue aims to provide an overview of the key topics in Schwann cell (SC) research, ranging from the latest discoveries in SC biology and development to the most recent applications of SC-based strategies for promoting the repair and regeneration of peripheral nerves. This Special Issue will be directed to a broad audience of both basic and clinical scientists and will address, among other things, such key topics as SC development, myelination, and remyelination, stem-cell-derived SCs, SC-enriched nerve prostheses, neuregulin/ErbB signaling, and SC-targeted gene therapy. The proposed deadline is November 30 2020.

Prof. Stefano Geuna
Guest Editor

Manuscript Submission Information

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Keywords

  • gliogenesis
  • schwann cell proliferation and differentiation
  • axon growth
  • wallerian degeneration
  • demyelination and remyelination
  • peripheral nerve repair
  • neurotrophic factors
  • neuregulin and ERB receptors
  • gene therapy
  • cell transplantation

Published Papers (10 papers)

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Research

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Article
N-Formylated Peptide Induces Increased Expression of Both Formyl Peptide Receptor 2 (Fpr2) and Toll-Like Receptor 9 (TLR9) in Schwannoma Cells—An In Vitro Model for Early Inflammatory Profiling of Schwann Cells
Cells 2020, 9(12), 2661; https://doi.org/10.3390/cells9122661 - 11 Dec 2020
Cited by 2 | Viewed by 1391
Abstract
Following nerve injury, disintegrated axonal mitochondria distal to the injury site release mitochondrial formylated peptides and DNA that can induce activation and inflammatory profiling of Schwann cells via formyl peptide receptor 2 (Fpr2) and toll-like receptor 9 (TLR9), respectively. We studied RT4 schwannoma [...] Read more.
Following nerve injury, disintegrated axonal mitochondria distal to the injury site release mitochondrial formylated peptides and DNA that can induce activation and inflammatory profiling of Schwann cells via formyl peptide receptor 2 (Fpr2) and toll-like receptor 9 (TLR9), respectively. We studied RT4 schwannoma cells to investigate the regulation of Fpr2 and TLR9 after stimulation with fMLF as a prototypical formylated peptide. RT4 cells were treated with fMLF at various concentrations and times with and without pretreatment with inhibitors (chloroquine for activated TLR9, PBP10 for Fpr2). Western blots of Fpr2, TLR9, p-p38, p-NFκB, and IL-6 were compared in relation to inflammatory profiling of RT4 cells and chemokine receptors (CCR2, CXCR4) as potential co-receptors of Fpr2. fMLF stimulation upregulated Fpr2 in RT4 cells at low concentrations (10 nM and 100 nM) but higher concentrations were required (10 µM and 50 µM) when the cells were pretreated with an activated TLR9 inhibitor. Moreover, the higher concentrations of fMLF could modulate TLR9 and inflammatory markers. Upregulation of Fpr2 triggered by 10 nM and 100 nM fMLF coincided with higher levels of chemokine receptors (CCR2, CXCR4) and PKCβ. Treating RT4 cells with fMLF, as an in vitro model of Schwann cells, uncovered Schwann cells’ complex responses to molecular patterns of release from injured axonal mitochondria. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Article
Modulation of Human Adipose Stem Cells’ Neurotrophic Capacity Using a Variety of Growth Factors for Neural Tissue Engineering Applications: Axonal Growth, Transcriptional, and Phosphoproteomic Analyses In Vitro
Cells 2020, 9(9), 1939; https://doi.org/10.3390/cells9091939 - 21 Aug 2020
Cited by 1 | Viewed by 1064
Abstract
We report on a potential strategy involving the exogenous neurotrophic factors (NTF) for enhancing the neurotrophic capacity of human adipose stem cells (ASC) in vitro. For this, ASC were stimulated for three days using NTF, i.e., nerve growth factor (NGF), brain-derived neurotrophic factor [...] Read more.
We report on a potential strategy involving the exogenous neurotrophic factors (NTF) for enhancing the neurotrophic capacity of human adipose stem cells (ASC) in vitro. For this, ASC were stimulated for three days using NTF, i.e., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), NT4, glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF). The resulting conditioned medium (CM) as well as individual NTF exhibited distinct effects on axonal outgrowth from dorsal root ganglion (DRG) explants. In particular, CM derived from NT3-stimulated ASC (CM-NT3-ASC) promoted robust axonal outgrowth. Subsequent transcriptional analysis of DRG cultures in response to CM-NT3-ASC displayed significant upregulation of STAT-3 and GAP-43. In addition, phosphoproteomic analysis of NT3-stimulated ASC revealed significant changes in the phosphorylation state of different proteins that are involved in cytokine release, growth factors signaling, stem cell maintenance, and differentiation. Furthermore, DRG cultures treated with CM-NT3-ASC exhibited significant changes in the phosphorylation levels of proteins involved in tubulin and actin cytoskeletal pathways, which are crucial for axonal growth and elongation. Thus, the results obtained at the transcriptional, proteomic, and cellular level reveal significant changes in the neurotrophic capacity of ASC following NT3 stimulation and provide new options for improving the axonal growth-promoting potential of ASC in vitro. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Article
Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCε in Peripheral Sensory Neurons
Cells 2020, 9(8), 1874; https://doi.org/10.3390/cells9081874 - 11 Aug 2020
Cited by 5 | Viewed by 1273
Abstract
Protein kinase type C-ε (PKCε) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKCε is modulated through the local release of mediators by the [...] Read more.
Protein kinase type C-ε (PKCε) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKCε is modulated through the local release of mediators by the surrounding Schwann cells (SCs). The progesterone metabolite allopregnanolone (ALLO) is endogenously synthesized by SCs, whereas it has proven to be a crucial mediator of neuron-glia interaction in peripheral nerve fibers. Biomolecular and pharmacological studies on rat primary SCs and dorsal root ganglia (DRG) neuronal cultures were aimed at investigating the hypothesis that ALLO modulates neuronal PKCε, playing a role in peripheral nociception. We found that SCs tonically release ALLO, which, in turn, autocrinally upregulated the synthesis of the growth factor brain-derived neurotrophic factor (BDNF). Subsequently, glial BDNF paracrinally activates PKCε via trkB in DRG sensory neurons. Herein, we report a novel mechanism of SCs-neuron cross-talk in the peripheral nervous system, highlighting a key role of ALLO and BDNF in nociceptor sensitization. These findings emphasize promising targets for inhibiting the development and chronification of neuropathic pain. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Article
Fibroblasts Colonizing Nerve Conduits Express High Levels of Soluble Neuregulin1, a Factor Promoting Schwann Cell Dedifferentiation
Cells 2020, 9(6), 1366; https://doi.org/10.3390/cells9061366 - 01 Jun 2020
Cited by 4 | Viewed by 916
Abstract
Conduits for the repair of peripheral nerve gaps are a good alternative to autografts as they provide a protected environment and a physical guide for axonal re-growth. Conduits require colonization by cells involved in nerve regeneration (Schwann cells, fibroblasts, endothelial cells, macrophages) while [...] Read more.
Conduits for the repair of peripheral nerve gaps are a good alternative to autografts as they provide a protected environment and a physical guide for axonal re-growth. Conduits require colonization by cells involved in nerve regeneration (Schwann cells, fibroblasts, endothelial cells, macrophages) while in the autograft many cells are resident and just need to be activated. Since it is known that soluble Neuregulin1 (sNRG1) is released after injury and plays an important role activating Schwann cell dedifferentiation, its expression level was investigated in early regeneration steps (7, 14, 28 days) inside a 10 mm chitosan conduit used to repair median nerve gaps in Wistar rats. In vivo data show that sNRG1, mainly the isoform α, is highly expressed in the conduit, together with a fibroblast marker, while Schwann cell markers, including NRG1 receptors, were not. Primary culture analysis shows that nerve fibroblasts, unlike Schwann cells, express high NRG1α levels, while both express NRG1β. These data suggest that sNRG1 might be mainly expressed by fibroblasts colonizing nerve conduit before Schwann cells. Immunohistochemistry analysis confirmed NRG1 and fibroblast marker co-localization. These results suggest that fibroblasts, releasing sNRG1, might promote Schwann cell dedifferentiation to a “repair” phenotype, contributing to peripheral nerve regeneration. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Review

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Review
Dynamic Environmental Physical Cues Activate Mechanosensitive Responses in the Repair Schwann Cell Phenotype
Cells 2021, 10(2), 425; https://doi.org/10.3390/cells10020425 - 17 Feb 2021
Viewed by 723
Abstract
Schwann cells plastically change in response to nerve injury to become a newly reconfigured repair phenotype. This cell is equipped to sense and interact with the evolving and unusual physical conditions characterizing the injured nerve environment and activate intracellular adaptive reprogramming as a [...] Read more.
Schwann cells plastically change in response to nerve injury to become a newly reconfigured repair phenotype. This cell is equipped to sense and interact with the evolving and unusual physical conditions characterizing the injured nerve environment and activate intracellular adaptive reprogramming as a consequence of external stimuli. Summarizing the literature contributions on this matter, this review is aimed at highlighting the importance of the environmental cues of the regenerating nerve as key factors to induce morphological and functional changes in the Schwann cell population. We identified four different microenvironments characterized by physical cues the Schwann cells sense via interposition of the extracellular matrix. We discussed how the physical cues of the microenvironment initiate changes in Schwann cell behavior, from wrapping the axon to becoming a multifunctional denervated repair cell and back to reestablishing contact with regenerated axons. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Review
Perspective on Schwann Cells Derived from Induced Pluripotent Stem Cells in Peripheral Nerve Tissue Engineering
Cells 2020, 9(11), 2497; https://doi.org/10.3390/cells9112497 - 17 Nov 2020
Cited by 10 | Viewed by 1380
Abstract
Schwann cells play a crucial role in successful peripheral nerve repair and regeneration by supporting both axonal growth and myelination. Schwann cells are therefore a feasible option for cell therapy treatment of peripheral nerve injury. However, sourcing human Schwann cells at quantities required [...] Read more.
Schwann cells play a crucial role in successful peripheral nerve repair and regeneration by supporting both axonal growth and myelination. Schwann cells are therefore a feasible option for cell therapy treatment of peripheral nerve injury. However, sourcing human Schwann cells at quantities required for development beyond research is challenging. Due to their availability, rapid in vitro expansion, survival, and integration within the host tissue, stem cells have attracted considerable attention as candidate cell therapies. Among them, induced pluripotent stem cells (iPSCs) with the associated prospects for personalized treatment are a promising therapy to take the leap from bench to bedside. In this critical review, we firstly focus on the current knowledge of the Schwann cell phenotype in regard to peripheral nerve injury, including crosstalk with the immune system during peripheral nerve regeneration. Then, we review iPSC to Schwann cell derivation protocols and the results from recent in vitro and in vivo studies. We finally conclude with some prospects for the use of iPSCs in clinical settings. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Review
Schwann Cell Role in Selectivity of Nerve Regeneration
Cells 2020, 9(9), 2131; https://doi.org/10.3390/cells9092131 - 20 Sep 2020
Cited by 13 | Viewed by 1696
Abstract
Peripheral nerve injuries result in the loss of the motor, sensory and autonomic functions of the denervated segments of the body. Neurons can regenerate after peripheral axotomy, but inaccuracy in reinnervation causes a permanent loss of function that impairs complete recovery. Thus, understanding [...] Read more.
Peripheral nerve injuries result in the loss of the motor, sensory and autonomic functions of the denervated segments of the body. Neurons can regenerate after peripheral axotomy, but inaccuracy in reinnervation causes a permanent loss of function that impairs complete recovery. Thus, understanding how regenerating axons respond to their environment and direct their growth is essential to improve the functional outcome of patients with nerve lesions. Schwann cells (SCs) play a crucial role in the regeneration process, but little is known about their contribution to specific reinnervation. Here, we review the mechanisms by which SCs can differentially influence the regeneration of motor and sensory axons. Mature SCs express modality-specific phenotypes that have been associated with the promotion of selective regeneration. These include molecular markers, such as L2/HNK-1 carbohydrate, which is differentially expressed in motor and sensory SCs, or the neurotrophic profile after denervation, which differs remarkably between SC modalities. Other important factors include several molecules implicated in axon-SC interaction. This cell–cell communication through adhesion (e.g., polysialic acid) and inhibitory molecules (e.g., MAG) contributes to guiding growing axons to their targets. As many of these factors can be modulated, further research will allow the design of new strategies to improve functional recovery after peripheral nerve injuries. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Review
Schwann Cell-Like Cells: Origin and Usability for Repair and Regeneration of the Peripheral and Central Nervous System
Cells 2020, 9(9), 1990; https://doi.org/10.3390/cells9091990 - 29 Aug 2020
Cited by 5 | Viewed by 1486
Abstract
Functional recovery after neurotmesis, a complete transection of the nerve fiber, is often poor and requires a surgical procedure. Especially for longer gaps (>3 mm), end-to-end suturing of the proximal to the distal part is not possible, thus requiring nerve graft implantation. Artificial [...] Read more.
Functional recovery after neurotmesis, a complete transection of the nerve fiber, is often poor and requires a surgical procedure. Especially for longer gaps (>3 mm), end-to-end suturing of the proximal to the distal part is not possible, thus requiring nerve graft implantation. Artificial nerve grafts, i.e., hollow fibers, hydrogels, chitosan, collagen conduits, and decellularized scaffolds hold promise provided that these structures are populated with Schwann cells (SC) that are widely accepted to promote peripheral and spinal cord regeneration. However, these cells must be collected from the healthy peripheral nerves, resulting in significant time delay for treatment and undesired morbidities for the donors. Therefore, there is a clear need to explore the viable source of cells with a regenerative potential similar to SC. For this, we analyzed the literature for the generation of Schwann cell-like cells (SCLC) from stem cells of different origins (i.e., mesenchymal stem cells, pluripotent stem cells, and genetically programmed somatic cells) and compared their biological performance to promote axonal regeneration. Thus, the present review accounts for current developments in the field of SCLC differentiation, their applications in peripheral and central nervous system injury, and provides insights for future strategies. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Review
Schwann Cell Cultures: Biology, Technology and Therapeutics
Cells 2020, 9(8), 1848; https://doi.org/10.3390/cells9081848 - 06 Aug 2020
Cited by 8 | Viewed by 1245
Abstract
Schwann cell (SC) cultures from experimental animals and human donors can be prepared using nearly any type of nerve at any stage of maturation to render stage- and patient-specific populations. Methods to isolate, purify, expand in number, and differentiate SCs from adult, postnatal [...] Read more.
Schwann cell (SC) cultures from experimental animals and human donors can be prepared using nearly any type of nerve at any stage of maturation to render stage- and patient-specific populations. Methods to isolate, purify, expand in number, and differentiate SCs from adult, postnatal and embryonic sources are efficient and reproducible as these have resulted from accumulated refinements introduced over many decades of work. Albeit some exceptions, SCs can be passaged extensively while maintaining their normal proliferation and differentiation controls. Due to their lineage commitment and strong resistance to tumorigenic transformation, SCs are safe for use in therapeutic approaches in the peripheral and central nervous systems. This review summarizes the evolution of work that led to the robust technologies used today in SC culturing along with the main features of the primary and expanded SCs that make them irreplaceable models to understand SC biology in health and disease. Traditional and emerging approaches in SC culture are discussed in light of their prospective applications. Lastly, some basic assumptions in vitro SC models are identified in an attempt to uncover the combined value of old and new trends in culture protocols and the cellular products that are derived. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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Other

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Perspective
How Does Protein Zero Assemble Compact Myelin?
Cells 2020, 9(8), 1832; https://doi.org/10.3390/cells9081832 - 04 Aug 2020
Viewed by 1326
Abstract
Myelin protein zero (P0), a type I transmembrane protein, is the most abundant protein in peripheral nervous system (PNS) myelin—the lipid-rich, periodic structure of membrane pairs that concentrically encloses long axonal segments. Schwann cells, the myelinating glia of the PNS, express P0 throughout [...] Read more.
Myelin protein zero (P0), a type I transmembrane protein, is the most abundant protein in peripheral nervous system (PNS) myelin—the lipid-rich, periodic structure of membrane pairs that concentrically encloses long axonal segments. Schwann cells, the myelinating glia of the PNS, express P0 throughout their development until the formation of mature myelin. In the intramyelinic compartment, the immunoglobulin-like domain of P0 bridges apposing membranes via homophilic adhesion, forming, as revealed by electron microscopy, the electron-dense, double “intraperiod line” that is split by a narrow, electron-lucent space corresponding to the extracellular space between membrane pairs. The C-terminal tail of P0 adheres apposing membranes together in the narrow cytoplasmic compartment of compact myelin, much like myelin basic protein (MBP). In mouse models, the absence of P0, unlike that of MBP or P2, severely disturbs myelination. Therefore, P0 is the executive molecule of PNS myelin maturation. How and when P0 is trafficked and modified to enable myelin compaction, and how mutations that give rise to incurable peripheral neuropathies alter the function of P0, are currently open questions. The potential mechanisms of P0 function in myelination are discussed, providing a foundation for the understanding of mature myelin development and how it derails in peripheral neuropathies. Full article
(This article belongs to the Special Issue Schwann Cells: From Formation to Clinical Significance)
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