Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of ...the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals.
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•Wound Schwann cells have a distinct dedifferentiation program•TGFβ signaling reprograms wound Schwann cells to invasive mesenchymal-like cells•TGFβ crosstalks with Eph signaling to drive collective Schwann cell migration•Loss of TGFβ signaling in Schwann cells delays nerve regeneration
Clements et al. show that the nerve-injury-induced Schwann cell dedifferentiation program is modulated by the wound microenvironment through TGFβ. TGFβ promotes regeneration by reprogramming Schwann cells to invasive, mesenchymal-like cells and crosstalking with Eph signaling to drive collective migration.
The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in ...instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.
Abstract Myelination of Schwann cells (SCs) is critical for the success of peripheral nerve regeneration, and biomaterials that can promote SCs' neurotrophin secretion as scaffolds are beneficial for ...nerve repair. Here we present a biomaterials-approach, specifically, a highly tunable conductive biodegradable flexible polyurethane by polycondensation of poly(glycerol sebacate) and aniline pentamer, to significantly enhance SCs' myelin gene expression and neurotrophin secretion for peripheral nerve tissue engineering. SCs are cultured on these conductive polymer films, and the biocompatibility of these films and their ability to enhance myelin gene expressions and sustained neurotrophin secretion are successfully demonstrated. The mechanism of SCs' neurotrophin secretion on conductive films is demonstrated by investigating the relationship between intracellular Ca2+ level and SCs' myelination. Furthermore, the neurite growth and elongation of PC12 cells are induced by adding the neurotrophin medium suspension produced from SCs-laden conductive films. These data suggest that these conductive degradable polyurethanes that enhance SCs' myelin gene expressions and sustained neurotrophin secretion perform great potential for nerve regeneration applications.
Abstract Chitosan is found to promote the regeneration of peripheral nerve system in our previous studies, whereas the regeneration speed is not satisfied with clinical request. Micropatterning could ...promote cell orientation and growth, however, the effect of porous chitosan micropatterning on nerve regeneration is rarely reported. In this study, the porous chitosan micropatterning with surface ridge/groove and inner porosity structure was fabricated using a combination of micromodeling and lyophilization method. The morphology and stability of the prepared chitosan micropatterning were evaluated, the regulation of Schwann cells behavior by chitosan micropatterning was evaluated. The results showed that the chitosan micropatterning displayed stripe-like structure with a clear and complete edge. The micropatterning with 30/30 μm was more stable than 20/20 μm sample. Schwann cells on chitosan micropatterning showed orientation adhesion and began to grow along a certain direction after culture for 2 h, and displayed the minimal orientation angle and the largest length/width ratio on 30/30 μm micropatterning after further culture for 3 d and 5 d, indicating the most obvious cell orientation. Moreover, the secretion of nerve growth factor (NGF) demonstrated that the micropatterned chitosan had no negative influence on the physiological function of Schwann cells. Thus, the results indicate that the porous chitosan micropatterning can regulate Schwann cell growth well, which may have potential application in nerve regeneration. The study provides an important basis for constructing porous nerve conduit with micropatterning structure in the inner wall.
An essential prerequisite for the survival of an organism is the ability to detect and respond to aversive stimuli. Current belief is that noxious stimuli directly activate nociceptive sensory nerve ...endings in the skin. We discovered a specialized cutaneous glial cell type with extensive processes forming a mesh-like network in the subepidermal border of the skin that conveys noxious thermal and mechanical sensitivity. We demonstrate a direct excitatory functional connection to sensory neurons and provide evidence of a previously unknown organ that has an essential physiological role in sensing noxious stimuli. Thus, these glial cells, which are intimately associated with unmyelinated nociceptive nerves, are inherently mechanosensitive and transmit nociceptive information to the nerve.
The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global ...regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.
► Schwann cell c-Jun is a master regulator of the PNS injury response ► c-Jun activates a defined repair program in Schwann cells of damaged nerves ► c-Jun controls transdifferentiation of differentiated Schwann cells to repair cells ► Schwann cell c-Jun is essential for neuronal survival and functional recovery
Unlike the central nervous system, injured peripheral nerves regenerate to restore function after injury. Arthur-Farraj et al. show that this repair potential depends on glial (Schwann) cell expression of the transcription factor c-Jun.
Schwann cells play a crucial role in successful nerve repair and regeneration by supporting both axonal growth and myelination. However, the sources of human Schwann cells are limited both for ...studies of Schwann cell development and biology and for the development of treatments for Schwann cell-associated diseases. Here, we provide a rapid and scalable method to produce self-renewing Schwann cell precursors (SCPs) from human pluripotent stem cells (hPSCs), using combined sequential treatment with inhibitors of the TGF-β and GSK-3 signaling pathways, and with neuregulin-1 for 18 days under chemically defined conditions. Within 1 week, hPSC-derived SCPs could be differentiated into immature Schwann cells that were functionally confirmed by their secretion of neurotrophic factors and their myelination capacity in vitro and in vivo. We propose that hPSC-derived SCPs are a promising, unlimited source of functional Schwann cells for treating demyelination disorders and injuries to the peripheral nervous system.
•hPSC-SCPs are highly expandable under chemically defined medium condition•hPSC-SCPs can rapidly and efficiently differentiate into functional Schwann cells•SCP-SCs myelinate axon and secrete various neurotrophic factors•SCP-SCs promote axonal regeneration in sciatic nerve-damaged mice
In this article, Cho and colleagues show that an efficient strategy for producing directly an unlimited supply of functional human Schwann cells (SCs) via successful derivation of expandable Schwann cell precursors (SCPs) from human pluripotent stem cells (hPSC-SCPs). Functional and molecular characteristic of SCs from hPSC-SCPs (SCP-SCs) were shown both in vitro and in vivo.
The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic ...injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.
In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss ...during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.
Fatty acid uptake and altered metabolism constitute hallmarks of metastasis
, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we ...show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood
. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.
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