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The role of peripheral nerve signaling in endometriosis.

ABSTRACT: A hallmark of endometriosis - a chronic debilitating condition whose causes are poorly understood - is neuronal innervation of lesions. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with endometriosis but also contribute to a pro-growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. The diverse array of contributions that neurons play in endometriosis indicate that it should be considered as a nerve-centric disease. This review is focused on the emerging field of exoneural biology and how it applies to the field of endometriosis, in particular the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the mechanisms of neuronal contribution to endometriosis, as well as their interactions with accompanying stromal and immune cells, will unearth novel disease-relevant pathways and targets, providing additional, more selective therapeutic horizons.

SUBMITTER: Godin SK

PROVIDER: S-EPMC8493968 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling.

Project description:BackgroundPeripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues.ResultsUsing newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve. Oppositely, progranulin deficient mice have long-lasting deficits in motor function tests after nerve injury due to enhanced losses of motor neurons and stronger microglia activation in the ventral horn of the spinal cord. Deep proteome and gene ontology (GO) enrichment analysis revealed that the proteins upregulated in progranulin overexpressing mice were involved in 'regulation of transcription' and 'response to insulin' (GO terms). Transcription factor prediction pointed to activation of Notch signaling and indeed, co-immunoprecipitation studies revealed that progranulin bound to the extracellular domain of Notch receptors, and this was functionally associated with higher expression of Notch target genes in the dorsal root ganglia of transgenic mice with neuronal progranulin overexpression. Functionally, these transgenic mice recovered normal gait and running, which was not achieved by controls and was stronger impaired in progranulin deficient mice.ConclusionWe infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery.

| S-EPMC5075406 | biostudies-literature

Role of macrophages in peripheral nerve injury and repair.

Project description:Resident and inflammatory macrophages are essential effectors of the innate immune system. These cells provide innate immune defenses and regulate tissue and organ homeostasis. In addition to their roles in diseases such as cancer, obesity and osteoarthritis, they play vital roles in tissue repair and disease rehabilitation. Macrophages and other inflammatory cells are recruited to tissue injury sites where they promote changes in the microenvironment. Among the inflammatory cell types, only macrophages have both pro-inflammatory (M1) and anti-inflammatory (M2) actions, and M2 macrophages have four subtypes. The co-action of M1 and M2 subtypes can create a favorable microenvironment, releasing cytokines for damaged tissue repair. In this review, we discuss the activation of macrophages and their roles in severe peripheral nerve injury. We also describe the therapeutic potential of macrophages in nerve tissue engineering treatment and highlight approaches for enhancing M2 cell-mediated nerve repair and regeneration.

| S-EPMC6524518 | biostudies-literature

Role of microtubule dynamics in Wallerian degeneration and nerve regeneration after peripheral nerve injury.

Project description:Wallerian degeneration, the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury, is essential for creating a permissive microenvironment for nerve regeneration, and involves cytoskeletal reconstruction. However, it is unclear whether microtubule dynamics play a role in this process. To address this, we treated cultured sciatic nerve explants, an in vitro model of Wallerian degeneration, with the microtubule-targeting agents paclitaxel and nocodazole. We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation, whereas nocodazole-induced microtubule destabilization inhibited these processes. Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration, as well as functional recovery of nerve conduction and target muscle and motor behavior, respectively. These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration. This study was approved by the Animal Care and Use Committee of Southern Medical University, China (approval No. SMU-L2015081) on October 15, 2015.

| S-EPMC8504388 | biostudies-literature

Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.

Project description: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.

| S-EPMC10722468 | biostudies-literature

Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer.

Project description:Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve transfer as a therapeutic option, as well as an adjunct therapy to transplantation of Schwann cells and their stem cell derivatives for repair of the damaged nerve. This review furthermore, will provide an elaborated discussion on the sources of Schwann cells, including sites to harvest their progenitor and stem cell lines. This reflects the accessibility to an additional, concurrent treatment approach with nerve transfers that, predicated on related research, may increase the efficacy of the current approach. We then discuss the experimental and clinical investigations of both Schwann cells and nerve transfer that are underway. Lastly, we provide the necessary consideration that these two lines of therapeutic approaches should not be exclusive, but conversely, should be pursued as a combined modality given their mutual role in peripheral nerve regeneration.

| S-EPMC5187901 | biostudies-literature

EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors.

Project description:Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics.

| S-EPMC3923530 | biostudies-literature

Role of interleukin-1β in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis.

Project description: Not available

| S-EPMC7192531 | biostudies-literature

Role of Electrical Stimulation in Peripheral Nerve Regeneration: A Systematic Review.

Project description:Functional recovery after peripheral nerve injury is often suboptimal despite the intrinsic permissive growth environment of the peripheral nervous system. The objective of this systematic review is to explore the use of electrical stimulation (ES) for peripheral nerve regeneration.MethodsA systematic literature search was conducted from inception to March 2, 2021 to retrieve articles on ES for peripheral nerve regeneration using the PubMed, Ovid MEDLINE, and Embase databases. Primary outcome measures included objective measures of motor and sensory nerve function.ResultsFour randomized control trials, two case reports, and three case series that addressed the aims were identified. The stimulation parameters varied greatly between studies, without an apparent commonality for a given electrical conduit. Outcomes measured included motor (n = 8) and sensory (n = 7) modalities (cold detection, static two-point discrimination, tactile discrimination, and pressure detection), nerve-specific muscle function and bulk, and electromyography (EMG) motor and sensory terminal latency. Different parameters for measurement were utilized and improvement was observed across the studies compared with controls (n = 4) or pre-intervention measurements (n = 5). One randomized control trial reported no benefit of ES and attributed their findings to their stimulation protocol. Complications were documented in three patients only and included wire remnant removal, skin pigmentation, and bone formation.ConclusionsES in peripheral nerve regeneration is beneficial in improving and accelerating recovery. A meta-analysis was not performed due to the heterogeneity, but all studies showed positive findings and minor to no complications. These results provide a primer for further development of delivery methods.

| S-EPMC8932473 | biostudies-literature

Localized regulation of axonal RanGTPase controls retrograde injury signaling in peripheral nerve.

Project description:Peripheral sensory neurons respond to axon injury by activating an importin-dependent retrograde signaling mechanism. How is this mechanism regulated? Here, we show that Ran GTPase and its associated effectors RanBP1 and RanGAP regulate the formation of importin signaling complexes in injured axons. A gradient of nuclear RanGTP versus cytoplasmic RanGDP is thought to be fundamental for the organization of eukaryotic cells. Surprisingly, we find RanGTP in sciatic nerve axoplasm, distant from neuronal cell bodies and nuclei, and in association with dynein and importin-alpha. Following injury, localized translation of RanBP1 stimulates RanGTP dissociation from importins and subsequent hydrolysis, thereby allowing binding of newly synthesized importin-beta to importin-alpha and dynein. Perturbation of RanGTP hydrolysis or RanBP1 blockade at axonal injury sites reduces the neuronal conditioning lesion response. Thus, neurons employ localized mechanisms of Ran regulation to control retrograde injury signaling in peripheral nerve.

| S-EPMC2538677 | biostudies-literature

EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting.

Project description:The peripheral nervous system has astonishing regenerative capabilities in that cut nerves are able to reconnect and re-establish their function. Schwann cells are important players in this process, during which they dedifferentiate to a progenitor/stem cell and promote axonal regrowth. Here, we report that fibroblasts also play a key role. Upon nerve cut, ephrin-B/EphB2 signaling between fibroblasts and Schwann cells results in cell sorting, followed by directional collective cell migration of Schwann cells out of the nerve stumps to guide regrowing axons across the wound. Mechanistically, we find that cell-sorting downstream of EphB2 is mediated by the stemness factor Sox2 through N-cadherin relocalization to Schwann cell-cell contacts. In vivo, loss of EphB2 signaling impaired organized migration of Schwann cells, resulting in misdirected axonal regrowth. Our results identify a link between Ephs and Sox proteins, providing a mechanism by which progenitor cells can translate environmental cues to orchestrate the formation of new tissue.

| S-EPMC3826531 | biostudies-literature

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