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Cellular and Molecular Life Sciences :... Oct 2020The 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... (Review)
Review
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.
Topics: Animals; Axons; Cell Plasticity; Humans; Myelin Sheath; Nerve Regeneration; Peripheral Nerve Injuries; Schwann Cells; Sciatic Nerve; Signal Transduction
PubMed: 32277262
DOI: 10.1007/s00018-020-03516-9 -
Neurobiology of Disease Jan 2023The glial cell of the peripheral nervous system (PNS), the Schwann cell (SC), counts among the most multifaceted cells of the body. During development, SCs secure... (Review)
Review
The glial cell of the peripheral nervous system (PNS), the Schwann cell (SC), counts among the most multifaceted cells of the body. During development, SCs secure neuronal survival and participate in axonal path finding. Simultaneously, they orchestrate the architectural set up of the developing nerves, including the blood vessels and the endo-, peri- and epineurial layers. Perinatally, in rodents, SCs radially sort and subsequently myelinate individual axons larger than 1 μm in diameter, while small calibre axons become organised in non-myelinating Remak bundles. SCs have a vital role in maintaining axonal health throughout life and several specialized SC types perform essential functions at specific locations, such as terminal SC at the neuromuscular junction (NMJ) or SC within cutaneous sensory end organs. In addition, neural crest derived satellite glia maintain a tight communication with the soma of sensory, sympathetic, and parasympathetic neurons and neural crest derivatives are furthermore an indispensable part of the enteric nervous system. The remarkable plasticity of SCs becomes evident in the context of a nerve injury, where SC transdifferentiate into intriguing repair cells, which orchestrate a regenerative response that promotes nerve repair. Indeed, the multiple adaptations of SCs are captivating, but remain often ill-resolved on the molecular level. Here, we summarize and discuss the knowns and unknowns of the vast array of functions that this single cell type can cover in peripheral nervous system development, maintenance, and repair.
Topics: Humans; Schwann Cells; Peripheral Nerves; Axons; Neurons; Peripheral Nervous System; Nerve Regeneration; Peripheral Nerve Injuries
PubMed: 36493976
DOI: 10.1016/j.nbd.2022.105952 -
Matrix Biology : Journal of the... Apr 2022Keloids are disfiguring, hypertrophic scars with yet poorly understood pathomechanisms, which could lead to severe functional impairments. Here we analyzed the...
Keloids are disfiguring, hypertrophic scars with yet poorly understood pathomechanisms, which could lead to severe functional impairments. Here we analyzed the characteristics of keloidal cells by single cell sequencing and discovered the presence of an abundant population of Schwann cells that persisted in the hypertrophic scar tissue after wound healing. In contrast to normal skin, keloidal Schwann cells show a unique, pro-fibrotic phenotype. Our data support the hypothesis that keloidal Schwann cells contribute to the formation of the extracellular matrix and are able to affect M2 polarization of macrophages. Indeed, we show that macrophages in keloids predominantly display a M2 polarization and produce factors that inhibit Schwann cell differentiation. This study suggests the contribution of a Schwann cell - macrophage cross-talk to the continuous expansion of keloids, and that targeting Schwann cells might represent an interesting novel treatment option for keloids.
Topics: Cicatrix, Hypertrophic; Extracellular Matrix; Humans; Keloid; Schwann Cells; Wound Healing
PubMed: 35278628
DOI: 10.1016/j.matbio.2022.03.001 -
Cell Metabolism Dec 2023The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on...
The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
Topics: Peripheral Nerves; Myelin Sheath; Neuroglia; Schwann Cells; Nerve Regeneration
PubMed: 37989315
DOI: 10.1016/j.cmet.2023.10.017 -
Nature Nov 2021Fatty acid uptake and altered metabolism constitute hallmarks of metastasis, yet evidence of the underlying biology, as well as whether all dietary fatty acids are...
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.
Topics: Animals; Cell Line, Tumor; Chromatin; Dietary Fats; Early Growth Response Protein 2; Extracellular Matrix; Female; Galanin; Histones; Humans; Male; Mice; Neoplasm Metastasis; Palmitic Acid; Schwann Cells
PubMed: 34759321
DOI: 10.1038/s41586-021-04075-0 -
Neurotherapeutics : the Journal of the... Oct 2021Myelin is a key evolutionary specialization and adaptation of vertebrates formed by the plasma membrane of glial cells, which insulate axons in the nervous system.... (Review)
Review
Myelin is a key evolutionary specialization and adaptation of vertebrates formed by the plasma membrane of glial cells, which insulate axons in the nervous system. Myelination not only allows rapid and efficient transmission of electric impulses in the axon by decreasing capacitance and increasing resistance but also influences axonal metabolism and the plasticity of neural circuits. In this review, we will focus on Schwann cells, the glial cells which form myelin in the peripheral nervous system. Here, we will describe the main extrinsic and intrinsic signals inducing Schwann cell differentiation and myelination and how myelin biogenesis is achieved. Finally, we will also discuss how the study of human disorders in which molecules and pathways relevant for myelination are altered has enormously contributed to the current knowledge on myelin biology.
Topics: Animals; Axons; Biology; Humans; Myelin Sheath; Neuroglia; Schwann Cells
PubMed: 34244924
DOI: 10.1007/s13311-021-01083-w -
JCI Insight Sep 2022To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop...
To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor-like (SCP-like) population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and Cd74, with sustained expression of the injury response gene Postn and showed dramatic expansion of immune and stromal cell populations; in corresponding human PNs, the immune and stromal cells comprised 90% of cells. Comparisons between injury-related and tumor monocytes/macrophages support early monocyte recruitment and aberrant macrophage differentiation. Cross-species analysis verified each SC population and unique conserved patterns of predicted cell-cell communication in each SC population. This analysis identified PROS1-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NF-κB as deregulated in NF1 SC populations, including SCP-like cells predicted to influence other types of SCs, stromal cells, and/or immune cells in mouse and human. These findings highlight remarkable changes in multiple types of SCs and identify therapeutic targets for PN.
Topics: Animals; Humans; Mice; NF-kappa B; Neurofibroma, Plexiform; Neurofibromatosis 1; Schwann Cells; Tumor Microenvironment
PubMed: 36134665
DOI: 10.1172/jci.insight.154513 -
The EMBO Journal Sep 2022Schwann cell precursors (SCPs) are nerve-associated progenitors that can generate myelinating and non-myelinating Schwann cells but also are multipotent like the neural...
Schwann cell precursors (SCPs) are nerve-associated progenitors that can generate myelinating and non-myelinating Schwann cells but also are multipotent like the neural crest cells from which they originate. SCPs are omnipresent along outgrowing peripheral nerves throughout the body of vertebrate embryos. By using single-cell transcriptomics to generate a gene expression atlas of the entire neural crest lineage, we show that early SCPs and late migratory crest cells have similar transcriptional profiles characterised by a multipotent "hub" state containing cells biased towards traditional neural crest fates. SCPs keep diverging from the neural crest after being primed towards terminal Schwann cells and other fates, with different subtypes residing in distinct anatomical locations. Functional experiments using CRISPR-Cas9 loss-of-function further show that knockout of the common "hub" gene Sox8 causes defects in neural crest-derived cells along peripheral nerves by facilitating differentiation of SCPs towards sympathoadrenal fates. Finally, specific tumour populations found in melanoma, neurofibroma and neuroblastoma map to different stages of SCP/Schwann cell development. Overall, SCPs resemble migrating neural crest cells that maintain multipotency and become transcriptionally primed towards distinct lineages.
Topics: Cell Differentiation; Neural Crest; Neurogenesis; Peripheral Nerves; Schwann Cells
PubMed: 35815410
DOI: 10.15252/embj.2021108780 -
Nature Communications Jul 2023Neuropathy is a feature more frequently observed in pancreatic ductal adenocarcinoma (PDAC) than other tumors. Schwann cells, the most prevalent cell type in peripheral...
Neuropathy is a feature more frequently observed in pancreatic ductal adenocarcinoma (PDAC) than other tumors. Schwann cells, the most prevalent cell type in peripheral nerves, migrate toward tumor cells and associate with poor prognosis in PDAC. To unveil the effects of Schwann cells on the neuro-stroma niche, here we perform single-cell RNA-sequencing and microarray-based spatial transcriptome analysis of PDAC tissues. Results suggest that Schwann cells may drive tumor cells and cancer-associated fibroblasts (CAFs) to more malignant subtypes: basal-like and inflammatory CAFs (iCAFs), respectively. Moreover, in vitro and in vivo assays demonstrate that Schwann cells enhance the proliferation and migration of PDAC cells via Midkine signaling and promote the switch of CAFs to iCAFs via interleukin-1α. Culture of tumor cells and CAFs with Schwann cells conditioned medium accelerates PDAC progression. Thus, we reveal that Schwann cells induce malignant subtypes of tumor cells and CAFs in the PDAC milieu.
Topics: Humans; Cancer-Associated Fibroblasts; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Schwann Cells; Tumor Microenvironment; Cell Line, Tumor; Fibroblasts
PubMed: 37524695
DOI: 10.1038/s41467-023-40314-w -
Cell Death & Disease Jan 2023Macrophage/microglia polarization acts as an important part in regulating inflammatory responses in spinal cord injury (SCI). However, the regulation of inflammation of...
Schwann cell-derived exosomes containing MFG-E8 modify macrophage/microglial polarization for attenuating inflammation via the SOCS3/STAT3 pathway after spinal cord injury.
Macrophage/microglia polarization acts as an important part in regulating inflammatory responses in spinal cord injury (SCI). However, the regulation of inflammation of Schwann cell-derived exosomes (SCDEs) for SCI repair is still unclear. Therefore, we intend to find out the effect of SCDEs on regulating the inflammation related to macrophage polarization during the recovery of SCI. Firstly, the thesis demonstrated that SCDEs could attenuate the LPS- inflammation in BMDMs by suppressing M1 polarization and stimulating M2 polarization. Similarly, SCDEs improved functional recovery of female Wistar rats of the SCI contusion model according to BBB (Basso, Beattie, and Bresnahan) score, electrophysiological assay, and the gait analysis system of CatWalk XT. Moreover, MFG-E8 was verified as the main component of SCDEs to improve the inflammatory response by proteomic sequencing and lentiviral transfection. Improvement of the inflammatory microenvironment also inhibited neuronal apoptosis. The knockout of MFG-E8 in SCs can reverse the anti-inflammatory effects of SCDEs treatment. The SOCS3/STAT3 signaling pathway was identified to participate in upregulating M2 polarization induced by MFG-E8. In conclusion, our findings will enrich the mechanism of SCDEs in repairing SCI and provide potential applications and new insights for the clinical translation of SCDEs treatment for SCI.
Topics: Rats; Animals; Female; Microglia; Exosomes; Proteomics; Rats, Wistar; Inflammation; Suppressor of Cytokine Signaling Proteins; Spinal Cord Injuries; Schwann Cells; Macrophages; Spinal Cord; Suppressor of Cytokine Signaling 3 Protein
PubMed: 36717543
DOI: 10.1038/s41419-023-05607-4