FOSL1 modulates Schwann cell responses in the wound microenvironment and regulates peripheral nerve regeneration
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE214449 | GEO | 2022/10/02
REPOSITORIES: GEO
Similar Datasets
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.
2017-08-30 | E-MTAB-5633 | biostudies-arrayexpress
Project description:After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes a significant clinical problem. We find that aging and chronically denervated repair cells express reduced c-Jun protein and the regenerative support provided by these cells is also reduced. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. These experiments reveal that a common mechanism, reduced c-Jun in repair cells, underlies two major reasons for regeneration failure in the PNS. They underscore the central importance of Schwann cell c-Jun as a regulator of nerve repair, and point to molecular pathways that can be manipulated for improving the clinical outcome of nerve injuries.
2020-10-14 | E-MTAB-9640 | biostudies-arrayexpress
Project description:The striking PNS regenerative response to injury rests on the plasticity of adult Schwann cells and their ability to transit between differentiation states, a highly unusual feature in mammals. Using mice with inactivation of Schwann cell c-Jun, we show that the injury response involves c-Jun dependent natural reprograming of differentiated cells to generate a distinct Schwann cell state specialized to promote regeneration. Transected distal stumps of c-Jun mutants show 172 disregulated genes, resulting in abnormal expression of growth factors, adhesion molecules and cytoskeletal changes that lead to neuronal death, inhibition of axon growth and striking failures of functional repair after injury. These observations provide a molecular basis for understanding Schwann cell plasticity and nerve regeneration. They offer conclusive support for the notion that Schwann cells control repair in the PNS, using dedicated transcriptional controls to generate a distinct repair cell, a transition that shows similarities to transdifferentiation seen in other systems. Total RNA was purified from a 10mm segment of the distal stump and uninjured contralateral nerve from c-Jun mutants and control mice 7 days after nerve cut. For each condition (injured/uninjured) and genotype (control/ knock-out) 2 independent samples (replicates) were generated from pooled nerves of 4/6 mice resulting in a total of 8 samples: CTRL.cut.R1, CTRL.cut.R2, CTRL.uncut.R1, CTRL.uncut.R2, KO.cut.R1, KO.cut.R2, KO.uncut.R1,KO.uncut.R2.
2012-06-13 | E-GEOD-38693 | biostudies-arrayexpress
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.
2023-12-12 | GSE244328 | GEO
Project description:The extracellular matrix is essential for tissue formation and regeneration through the control of cellular behavior. Deregulation of extracellular matrix components is associated to disease, including neurodegeneration. After peripheral nerve injury, Schwann cells guide regrowing axons to their targets. These glial cells migrate collectively and provide an extracellular environment to enable neural repair. How this occurs remains poorly understood. Here, we show that Sox2 controls fibronectin fibrillogenesis in Schwann cells to provide a highly oriented extracellular matrix, which supports their rapid collective migration with a continuous cellular flow. Sox2 directly activates fibronectin expression in Schwann cells, leading to an increase in fibrillogenesis and cellular huddling. Accordingly, loss of fibrillogenesis leads to glial disassembly and disorganized axon regrowth. In vivo, 7 days post nerve injury, we found that pro-regenerative Schwann cells co-express Sox2 and the EIIIA-containing fibronectin splicing isoform. This mechanism is conserved in mammals, including humans, but absent in zebrafish. Taken together, our results demonstrate that Sox2 directly controls fibrillogenesis and provide a novel mechanism for the modification of the environmental architecture by glial cells during neuronal repair.
2020-02-11 | GSE94590 | GEO
Project description:The striking PNS regenerative response to injury rests on the plasticity of adult Schwann cells and their ability to transit between differentiation states, a highly unusual feature in mammals. Using mice with inactivation of Schwann cell c-Jun, we show that the injury response involves c-Jun dependent natural reprograming of differentiated cells to generate a distinct Schwann cell state specialized to promote regeneration. Transected distal stumps of c-Jun mutants show 172 disregulated genes, resulting in abnormal expression of growth factors, adhesion molecules and cytoskeletal changes that lead to neuronal death, inhibition of axon growth and striking failures of functional repair after injury. These observations provide a molecular basis for understanding Schwann cell plasticity and nerve regeneration. They offer conclusive support for the notion that Schwann cells control repair in the PNS, using dedicated transcriptional controls to generate a distinct repair cell, a transition that shows similarities to transdifferentiation seen in other systems.
2012-06-14 | GSE38693 | GEO
Project description:The peripheral nervous system (PNS) regenerates after injury. However regeneration is often compromised in case of large lesions, the speed of axon reconnection to their target being critical for successful functional recovery. After injury, mature Schwann cells (SCs) convert into repair cells that foster axonal regrowth, and redifferentiate to rebuild myelin. These processes require the regulation of several transcription factors, but the driving mechanisms remain partially understood. Here, we identify an early response to injury controlled by histone deacetylase (HDAC)2, which coordinates the action of other chromatin-remodeling enzymes to induce the upregulation of Oct6, a key transcription factor for Schwann cell development. Inactivating this mechanism using mouse genetics allows earlier conversion into repair cells and leads to faster axonal regrowth, but impairs remyelination. Consistently, short-term HDAC1/2 inhibitor treatment early after lesion accelerates functional recovery and enhances regeneration, thereby identifying a new therapeutic strategy to improve PNS regeneration after lesion.
2018-10-17 | PXD005383 | Pride
Project description:Since Schwann cells (SCs) support axonal growth at development as well as after peripheral nerve injury (PNI), developing SCs might be able to promote axon regeneration after PNI. The purpose of the current study was to elucidate the capability of developing SCs to induce axon regeneration after PNI. SC precursors (SCPs), immature SCs (ISCs), repair SCs (RSCs) from injured nerves, and non-RSCs from intact nerves were tested by grafting into acellular region of rat sciatic nerve with crush injury. Both of developing SCs completely failed to support axon regeneration, whereas both of mature SCs, especially RSCs, induced axon regeneration. Further, RSCs but not SCPs promoted neurite outgrowth of adult dorsal root ganglion neurons. Transcriptome analysis revealed that the gene expression profiles were distinctly different between RSCs and SCPs. These findings indicate that developing SCs are markedly different from mature SCs in terms of functional and molecular aspects and that RSC is a viable candidate for regenerative cell therapy for PNI.
2022-01-13 | GSE188399 | GEO
Project description:The important contribution of glia to mechanisms of injury and repair of the nervous system is increasingly recognized. In stark contrast to the central nervous system (CNS), the peripheral nervous system (PNS) has a remarkable capacity for regeneration after injury. Schwann cells are recognized as key contributors to PNS regeneration but the molecular underpinnings of the Schwann cell response to injury remain incompletely understood. To gain insight into the acute SC injury response, we provide an RNAseq database of Schwann cells purified acutely from the naïve and injured rodent sciatic nerve at 3, 5, and 7 days post injury. Bioinformatic analysis provides validation of cell purity and dataset integrity as well as identification of discrete modules of genes that follow distinct patterns of regulation in the first days after injury and their corresponding molecular pathways. Our dataset provides a helpful resource for further deciphering the SC injury response and provides a depth of transcriptional data that can complement the findings of recent single cell sequencing approaches. In addition, as more data becomes available on the response of CNS glia to injury, we anticipate that this dataset will provide a valuable platform for understanding key differences in the PNS and CNS glial responses to injury and for designing approaches to ameliorate CNS regeneration.
2022-05-10 | GSE177037 | GEO
Project description:The current understanding is that Schwann cell transplantation is ideal strategy for peripheral nerve regeneration instead of autograft. It is difficult to obtain the required amount of Schwann cells which are best transplant condition, and central nervous cells have been gained attention in recent years, but its regenerative mechanism remain unknown. Neural stem/progenitor cells (NSPC) can generate various type of neural lineage cells (NLCs), and NSPCs derived from pluripotent stem cells are promising cells for cell therapy for neurodegenerative diseases. However, more safe and accessible cell source of NSPCs are required. In this study, we aim to provide NLCs derived from human dental pulp stem cells (DPSCs), and reveal the mechanism involved in regeneration after NLCs transplantation into peripheral nerve defect. Here, characterization of NLCs, paracrine effects for endothelial cells and Schwann cells, in xenotransplant for rat 10mm sciatic nerve defect, the differentiation, the survival, and outcome of nerve regeneration were investigated. Induced NLCs consisted of neuronal lineage cells, astrocyte lineage cells, oligodendrocyte lineage cells, and neural crest lineage cells. Considering retrospectively, NLCs were possible derived from NSPCs. Microarray analysis revealed neural markers of primary embryological development were up-regulated in induced NLCs compared to DPSCs. Moreover, NLCs enhanced the activity of endothelial cells and Schwann cells by paracrine effects in vitro. Two weeks after transplantation, many transplanted NLCs differentiated into platelet-derived growth factor receptor alpha (PDGFRa) + oligodendrocyte progenitor cells (OPCs), and PDGFRa+/p75 neurotrophin receptor + Schwann cells derived from OPCs were observed. Twelve weeks after transplantation, NLCs promoted functional repair of peripheral nerve. A few human Schwann cells survived, but did not myelinate axon. These findings suggest that some of mechanism promoting for peripheral nerve regeneration by transplanted NLCs. Transplantation of NLCs derived from DPSCs into partial peripheral nerve defect may be widely used for further experiments.
2021-03-07 | GSE168399 | GEO