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Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

ABSTRACT: 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.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Rhona Mirsky

PROVIDER: E-MTAB-9640 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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c-JUN REPROGRAMS SCHWANN CELLS OF INJURED NERVES TO GENERATE A REPAIR CELL ESSENTIAL FOR REGENERATION

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

Matrix metalloproteinase-9 and TIMP-1 in peripheral nerve: Implications for myelin formation

Project description:Remyelination is a key step in functional nerve regeneration performed by Schwann cells (SC). We have demonstrated that matrix metalloproteinase (MMP)-9 is a major regulator of signal transduction and phenotypic switching in SCs. Herein, genome-wide transcriptional profiling, followed by Ingenuity Pathway Analysis revealed the MMP-9 signaling network and its endogenous inhibitor, TIMP-1, among the top induced genes of the injured sciatic nerve, that co-distributed with MMP-9 in myelinating SCs and the paranodal/nodal areas of myelinated fibers. Homo- and heterodimers of the active and proMMP-9 were purified from injured nerves using gelatin-sepharose. MMP-9 gene deletion increased the number of immature, GFAP+ mSC and post-mitotic cell counts that correlate with shorter myelin internodes in remyelinated fibers lacking MMP-9. MMP-9 is essential to nodal clustering of voltage-gated Na+ (Nav) channels. MMP inhibitor therapy diminished the expression of Nav 1.7 and 1.8. These data established the essential role of MMP-9 in guiding SC differentiation toward myelin production and in molecular assembly of the myelin domains. Modification of Nav channels in myelinated fibers may thus provide an important therapeutic approach for a number of facilitates regeneration and attenuated neuropathic pain. Gene expression profiling of total RNAs extracted from murine sciatic nerves, dorsal root ganglion and spinal cords at day 1 and day 5 post injury.

2012-02-28 | E-GEOD-33454 | biostudies-arrayexpress

Histone H3K4 trimethylation in rat peripheral nerve

Project description:ChIP-seq of H3K4me3 in rat peripheral nerve was used to identify transcription start sites associated with Schwann cell-expressed genes. The analysis was performed in injured and control nerve to identify injury-responsive changes in Schwann cells. H3K4me3 ChIP samples were prepared from rat sciatic nerve at 1 day post-transection using both the distal stump of the injured nerve and the contralateral (sham) nerve.

2016-08-01 | E-GEOD-84272 | biostudies-arrayexpress

Changes in the coding/non-coding transcriptome and DNA methylome that define the Schwann cell repair phenotype after nerve injury

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

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2012-05-06 | E-GEOD-25863 | biostudies-arrayexpress

Rat motor and sensory nerve LC-MSMS

Project description:Peripheral nerve repair and functional recovery depend on the rate of nerve regeneration and the quality of target reinnervation. It is important to fully understand the cellular and molecular basis underlying the specificity of peripheral nerve regeneration, which means the achieving of respective correct pathfinding and accurate target reinnervation for regrowing motor and sensory axons. In this study, a quantitative proteomic technique, based on isobaric tags for relative and absolute quantitation (iTRAQ) was used to profile the protein expression pattern between single motor and sensory nerves at 14 days after peripheral nerve transection. Among a total of 1259 proteins identified, 176 proteins showed the differential expressions between injured motor and sensory nerves. Quantitative real-time RT-PCR and Western blot analysis were applied to validate the proteomic data on representative differentially expressed proteins. Functional categorization indicated that differentially expressed proteins were linked to a diverse array of molecular functions, including axonogenesis, response to axon injury, tissue remodeling, axon ensheathment, cell proliferation and adhesion, vesicle-mediated transport, response to oxidative stress, internal signal cascade, and macromolecular complex assembly, which might play an essential role in peripheral motor and sensory nerve regeneration. Overall, we hope that the proteomic database obtained in this study could serve as a solid foundation for the comprehensive investigation of differentially expressed proteins between injured motor and sensory nerves and for the mechanism elucidation of the specificity of peripheral nerve regeneration.

2020-12-10 | PXD022097 | Pride

Comparative proteomics analysis of growth-primed adult dorsal root ganglia reveals key molecular mediators for peripheral nerve regeneration

Project description:Peripheral nerve injuries due to physical insults or chronic diseases are quite common, yet no pharmacological therapies are available for the effective repair of injured nerves. The slow growth rate of adult nerves and insufficient access to growth factors pose major hurdles in timely reinnervating target tissues and restoring functions after nerve injuries. A better understanding of the molecular changes that occur during the immediate regenerative reprogramming of neurons, stated here as in vivo priming, following nerve injury may reveal ideal candidates for future therapies. Hence, molecular profiling of neuronal soma within the first week of nerve injury has been the gold standard for revealing molecular candidates critical for nerve regeneration. A complementary in vitro regenerative priming approach was recently shown to induce enhanced outgrowth in adult sensory neurons. In this work, we exploited the in vitro priming model to reveal novel candidates for adult nerve regeneration. We performed the whole tissue proteomics analysis of in vitro primed DRGs and compared their molecular profile with that of the in vivo primed, and control DRGs. Through this approach, we identified several commonly and uniquely altered molecules in the in vitro and in vivo primed DRGs that have the potential to modulate adult nerve regrowth. We further validated the growth inducing potential of mesencephalic astrocyte-derived neurotrophic factor (MANF), one of the hits identified in our proteomics analysis, in primary adult sensory neurons. Overall, this study showed that in vitro priming partially reproduces the molecular features in in vivo primed adult sensory neurons. The shortlisted candidates presented here from the two priming approaches may serve as potential therapeutic targets for adult nerve regeneration.

2023-01-06 | PXD031927 | Pride

Transcription profiling of human Schwann cells after extended exposure to heregulin and forskolin

Project description:Schwann cells, expanded in number by exposure to growth factors in vitro, could be useful in nervous system repair. Our previous results suggest that long term exposure to heregulin and forskolin changes the functional properties of the human Schwann cells, including the ability to myelinate axons after transplantation. Here, we propose to determine the molecular changes in the Schwann cells that occur as a result of extended growth with mitogenic factors. We believe that the information obtained in these studies will provide clues about mechanisms underlying the already observed changes in function. This information will aid in the prediction of the safety and efficacy of neural repair approaches that use cultured, expanded Schwann cells. Finally this data may provide clues into the mechanisms underlying normal human Schwann cell function.,To use gene array analysis to compare gene expression profiles in early and late passage human Schwann cells exposed to the growth factors heregulin and forskolin.,Observed changes in the function of human Schwann cells, including their capacity for growth and differentiation, after prolonged exposure to heregulin and forskolin, are caused by changes in the gene expression profiles in these cells.

2007-06-22 | E-GEOD-4030 | biostudies-arrayexpress

Gene expression in mouse DRG neurons at 2 or 5 days post-sciatic lesion in WT and Nfil3-KO

Project description:Mice with a deletion of transcription factor Nfil3 show delayed functional regeneration after sciatic lesion compared to WT mice. To analyze differential gene expression, sciatic nerves were lesioned and nerve endings were coaptated. After two or 5 days, DRGs L4 and L5 were dissected out and gene expression was measured by microarray. Control tissue was taken from the non-injured side. We found that expression of classic regeneration associated genes was similar in WT and Nfil3 KO mice. We did identify a group of differentially expressed genes known for its role in olfactory signal transduction, but were not known as regeneration associated genes until now, which may explain the negative effects on functional recovery. Gene expression in DRGs L4 and L5 from WT and NFIL3 KO mice was analyzed at 2 and 5 days after receiving a sciatic nerve lesion. Control tissue was taken from the non-injured side. Four biological replicates were used per condition. Microarray chips were two color chips, but each channel was analyzed in single color fashion. Conditions were pseudo-randomized over chips in a balanced dye-swap setup.

2015-02-25 | E-GEOD-66259 | biostudies-arrayexpress

Solexa sequencing of small RNAs in Sprague-Dawley (SD) rat [proximal sciatic nerve]

Project description:We applied Solexa sequencing technology to identify rat microRNA genes in proximal sciatic nerve following sciatic nerve resection. Using Solexa sequencing, computational analysis and Q-PCR verification, 93 novel miRNAs in rats were discovered and identified, of which 42 novel miRNAs were first reported in proximal sciatic nerve of rat and 51 novel miRNAs were produced at days 1, 4, 7 and 14 after sciatic nerve resection. These data provide an important resource relating to the role and regulation of miRNAs for future studies relating to peripheral nerve injury and regeneration. Keywords: Small RNA sequencing 18-30 nt small RNAs from proximal sciatic nerve of 30 Thirty Sprague-Dawley (SD) rats were sequenced at one Solexa lane

2012-05-06 | E-GEOD-26753 | biostudies-arrayexpress

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