Changes in the Coding and Non-coding Transcriptome and DNA Methylome that Define the Schwann Cell Repair Phenotype after Nerve Injury

Arthur‐Farraj, Peter; Morgan, Claire C.; Adamowicz, Martyna; Gomez-Sanchez, Jose A.; Fazal, Shaline V.; Beucher, Anthony; Razzaghi, Bonnie; Mirsky, Rhona; Jessen, Kristján R.; Aitman, Timothy J.

doi:10.1016/j.celrep.2017.08.064

Cited by 164 publications

(199 citation statements)

References 55 publications

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“…Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org). Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org).…”

Section: Rna-seq Analysis Of Human Skin Biopsiesmentioning

confidence: 99%

“…Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org). 46,47 Many SC genes associated with myelination change dramatically after peripheral nerve injury in rodent models, 37,42 but Gldn expression does not change after injury. In a trial analysis to normalize PMP22 levels to SC content, we used Gliomedin (GLDN), which is a SC-specific gene ( Supplementary Fig 2) involved in the formation of nodes of Ranvier.…”

Section: Rna-seq Analysis Of Human Skin Biopsiesmentioning

confidence: 99%

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Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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Objective: Charcot-Marie-Tooth (CMT) disease is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls. One complicating factor is the variable amounts of Schwann cells (SCs) in skin. The objective of the study was to develop a novel method for precise evaluation of PMP22 levels in skin biopsies that can discriminate CMT1A patients from controls. Methods: We have developed methods to normalize PMP22 transcript levels to SC-specific genes that are not altered by CMT1A status. Several CMT1A-associated genes were assembled into a custom Nanostring panel to enable precise transcript measurements that can be normalized to variable SC content. Results: The digital expression data from Nanostring analysis showed reproducible elevation of PMP22 levels in CMT1A versus control skin biopsies, particularly after normalization to SC-specific genes. Interpretation: This platform should be useful in clinical trials for CMT1A as a biomarker of target engagement that can be used to optimize dosing, and the same normalization framework is applicable to other types of CMT.

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Section: Rna-seq Analysis Of Human Skin Biopsiesmentioning

confidence: 99%

“…Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org). 46,47 Many SC genes associated with myelination change dramatically after peripheral nerve injury in rodent models, 37,42 but Gldn expression does not change after injury. In a trial analysis to normalize PMP22 levels to SC content, we used Gliomedin (GLDN), which is a SC-specific gene ( Supplementary Fig 2) involved in the formation of nodes of Ranvier.…”

Section: Rna-seq Analysis Of Human Skin Biopsiesmentioning

confidence: 99%

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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“…A recent contribution to this debate, namely the identification of partial epithelial–mesenchymal transition (EMT) in injured nerves (Arthur‐Farraj et al, ; Clements et al, ), highlights how our understanding of the Schwann cell injury response has progressed by degrees, with each step providing new insights into this complex process.…”

Section: Introduction: the Changing View On The Schwann Cell Injury Rmentioning

confidence: 99%

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

Jessen

Arthur‐Farraj

2019

Glia

224

229

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Schwann cells respond to nerve injury by cellular reprogramming that generates cells specialized for promoting regeneration and repair. These repair cells clear redundant myelin, attract macrophages, support survival of damaged neurons, encourage axonal growth, and guide axons back to their targets. There are interesting parallels between this response and that found in other tissues. At the cellular level, many other tissues also react to injury by cellular reprogramming, generating cells specialized to promote tissue homeostasis and repair. And at the molecular level, a common feature possessed by Schwann cells and many other cells is the injury‐induced activation of genes associated with epithelial–mesenchymal transitions and stemness, differentiation states that are linked to cellular plasticity and that help injury‐induced tissue remodeling. The number of signaling systems regulating Schwann cell plasticity is rapidly increasing. Importantly, this includes mechanisms that are crucial for the generation of functional repair Schwann cells and nerve regeneration, although they have no or a minor role elsewhere in the Schwann cell lineage. This encourages the view that selective tools can be developed to control these particular cells, amplify their repair supportive functions and prevent their deterioration. In this review, we discuss the emerging similarities between the injury response seen in nerves and in other tissues and survey the transcription factors, epigenetic mechanisms, and signaling cascades that control repair Schwann cells, with emphasis on systems that selectively regulate the Schwann cell injury response.

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“…Additionally, we show that supernatant of ESWT‐treated Schwann cell cultures is significantly more potent in inducing neurites in vitro. This could be explained by an increased and prolonged induction of c‐jun and subsequent secretion of neurotrophic factor production, as other groups have shown that c‐jun activation results in a strong induction of pro‐regenerative genes …”

Section: Discussionmentioning

confidence: 97%

Motor and sensory Schwann cell phenotype commitment is diminished by extracorporeal shockwave treatment in vitro

Hercher

Redl

Schuh

2020

J Peripheral Nervous Sys

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The gold standard for peripheral nerve regeneration uses a sensory autograft to bridge a motor/sensory defect site. For motor nerves to regenerate, Schwann cells (SC) myelinate the newly grown axon. Sensory SCs have a reduced ability to produce myelin, partially explaining low success rates of autografts. This issue is masked in pre‐clinical research by the excessive use of the rat sciatic nerve defect model, utilizing a mixed nerve with motor and sensory SCs. Aim of this study was to utilize extracorporeal shockwave treatment as a novel tool to influence SC phenotype. SCs were isolated from motor, sensory and mixed rat nerves and in vitro differences between them were assessed concerning initial cell number, proliferation rate, neurite outgrowth as well as ability to express myelin. We verified the inferior capacity of sensory SCs to promote neurite outgrowth and express myelin‐associated proteins. Motor Schwann cells demonstrated low proliferation rates, but strongly reacted to pro‐myelination stimuli. It is noteworthy for pre‐clinical research that sciatic SCs are a strongly mixed culture, not representing one or the other. Extracorporeal shockwave treatment (ESWT), induced in motor SCs an increased proliferation profile, while sensory SCs gained the ability to promote neurite outgrowth and express myelin‐associated markers. We demonstrate a strong phenotype commitment of sciatic, motor, and sensory SCs in vitro, proposing the experimental use of SCs from pure cultures to better mimic clinical situations. Furthermore we provide arguments for using ESWT on autografts to improve the regenerative capacity of sensory SCs.

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Changes in the Coding and Non-coding Transcriptome and DNA Methylome that Define the Schwann Cell Repair Phenotype after Nerve Injury

Cited by 164 publications

References 55 publications

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

Motor and sensory Schwann cell phenotype commitment is diminished by extracorporeal shockwave treatment in vitro

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