Delay Modulates the Immune Response to Nerve Repair
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA897851 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22175600.fastq.gz | Fastqsanger.gz | |||
| SRR22175601.fastq.gz | Fastqsanger.gz | |||
| SRR22175602.fastq.gz | Fastqsanger.gz | |||
| SRR22175603.fastq.gz | Fastqsanger.gz | |||
| SRR22175604.fastq.gz | Fastqsanger.gz |
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Project description:Effective regeneration after peripheral nerve injury requires macrophage recruitment. We investigated activation of remodeling pathways within the macrophage population when repair is delayed and identified alteration of key upstream regulators of the inflammatory response. We then targeted one of these regulators, using exogenous IL10 to manipulate the response to injury at the repair site. We demonstrate that this approach alters macrophage polarization, promotes macrophage recruitment, axon extension, neuromuscular junction formation and increases the number of regenerating motor units reaching their target. We also demonstrate that this approach can rescue the effects of delayed nerve graft.
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Project description:Effective regeneration after peripheral nerve injury requires macrophage recruitment. We investigated the activation of remodeling pathways within the macrophage population when repair is delayed and identified alteration of key upstream regulators of the inflammatory response. We then targeted one of these regulators, using exogenous IL10 to manipulate the response to injury at the repair site. We demonstrate that this approach alters macrophage polarization, promotes macrophage recruitment, axon extension, neuromuscular junction formation, and increases the number of regenerating motor units reaching their target. We also demonstrate that this approach can rescue the effects of delayed nerve graft.
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Project description:Schwann cell (Büngner) repair cells play a critical role in orchestrating nerve repair after injury, but the reprogramming process that generates them is poorly understood. We present the first combined whole genome coding and non-coding RNA and CpG methylation study after nerve injury. We show that genes involved in epithelial to mesenchymal transition are enriched in repair cells and we identify long non-coding RNAs in Schwann cells. We demonstrate that the AP-1 transcription factor c-Jun regulates the expression of certain micro RNAs in repair cells, in particular miR-21 and miR-34. Surprisingly, changes in CpG methylation are limited in injury, unlike development, and restricted to specific locations, such as enhancer regions of novel Schwann cell specific genes, such as Nedd4l, and near to local enrichment of AP-1 motifs. These epigenetic changes significantly broaden our understanding of Schwann cell reprogramming in peripheral nervous system tissue repair. To identify epigenetic regulators underlying successful nerve regeneration we generated RNA-Seq, small-RNA-Seq and whole genome bisulfite sequencing libraries for uninjured nerve versus three and/or seven day post nerve transection sciatic nerves of adult C57BL/6J mice crush.
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Project description:Entospletinib modulates spatial gene expression in kidney immune microenvironments during injury and repair
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Project description:The peripheral nervous system harbours 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 break down 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.
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Project description:Peripheral glial Schwann cells switch to a repair state after nerve injury, proliferate to supply lost cell population, migrate to form regeneration tracks, and generates a permissive microenvironment for nerve regeneration. Exploring essential regulators of the repair responses of Schwann cells may benefit the clinical treatment for peripheral nerve injury. In the present study, FOSL1 regulates Schwann cell phenotype modulation and provided a novel therapeutic approach to orchestrate the regeneration and functional recovery of injured peripheral nerves.
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Project description:After peripheral nerve injury, adult Schwann cells convert to progenitor cell-like repair Schwann cells, which are pivotal for nerve regeneration. We show that Schwann cell-specific deletion of TFEB/3 disrupts the transcriptomic reprogramming necessary for injury-induced repair Schwann cell generation in mice. The mutant mice fail to generate proliferating repair Schwann cells to populate the injured nerves. Distal Schwann cells fail to express injury-responsive genes and continue to maintain the expression of myelin-associated genes. TFEB/3 binding motifs are enriched in injury-induced enhancers, suggesting their role in repair gene activation. Autophagy-dependent myelin breakdown is not impaired in the mutant mice despite the known function of TFEB/3 as autophagy activators. However, the mutant mice exhibit defects in axon regeneration, target reinnervation, and functional recovery. Therefore, TFEB/3 play a critical role in orchestrating transcriptional changes essential for repair Schwann cell generation and function necessary for peripheral nerve regeneration.
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Project description:The remarkable feature of Schwann cells (SCs) to transform into a repair phenotype turned the spotlight on this powerful cell type. SCs provide the regenerative environment for axonal re-growth after peripheral nerve injury (PNI) and play a vital role in differentiation of neuroblastic tumors into a benign subtype of neuroblastoma, a tumor originating from neural crest-derived neuroblasts. Hence, understanding their mode-of-action is of utmost interest for new approaches in regenerative medicine, but also for neuroblastoma therapy. However, literature on human SCs is scarce and it is unknown to which extent human SC cultures reflect the SC repair phenotype developing after PNI in patients. We performed high-resolution proteome profiling and RNA-sequencing on highly enriched human SC and fibroblast cultures, control and ex vivo degenerated nerve explants to identify novel molecules and functional processes active in repair SCs. In fact, we found cultured SCs and degenerated nerves to share a similar repair SC-associated expression signature, including the upregulation of JUN, as well as two prominent functions, i.e., myelin debris clearance and antigen presentation via MHCII. In addition to myelin degradation, cultured SCs were capable of actively taking up cell-extrinsic components in functional phagocytosis and co-cultivation assays. Moreover, in cultured SCs and degenerated nerve tissue MHCII was upregulated at the cellular level along with high expression of chemoattractants and co-inhibitory rather than -stimulatory molecules. These results demonstrate human SC cultures to execute an inherent program of nerve repair and support two novel repair SC functions, debris clearance via phagocytosis-related mechanisms and type II immune-regulation.
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