Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury

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Abstract

The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.

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Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.

Marie Cargnello, Philippe Roux (2011)

The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.

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Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.

Abhishek K. Jha, Stanley Ching-Cheng Huang, Alexey Sergushichev … (2015)

Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.

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The repair Schwann cell and its function in regenerating nerves

K. Jessen, R Mirsky (2016)

Abstract Nerve injury triggers the conversion of myelin and non‐myelin (Remak) Schwann cells to a cell phenotype specialized to promote repair. Distal to damage, these repair Schwann cells provide the necessary signals and spatial cues for the survival of injured neurons, axonal regeneration and target reinnervation. The conversion to repair Schwann cells involves de‐differentiation together with alternative differentiation, or activation, a combination that is typical of cell type conversions often referred to as (direct or lineage) reprogramming. Thus, injury‐induced Schwann cell reprogramming involves down‐regulation of myelin genes combined with activation of a set of repair‐supportive features, including up‐regulation of trophic factors, elevation of cytokines as part of the innate immune response, myelin clearance by activation of myelin autophagy in Schwann cells and macrophage recruitment, and the formation of regeneration tracks, Bungner's bands, for directing axons to their targets. This repair programme is controlled transcriptionally by mechanisms involving the transcription factor c‐Jun, which is rapidly up‐regulated in Schwann cells after injury. In the absence of c‐Jun, damage results in the formation of a dysfunctional repair cell, neuronal death and failure of functional recovery. c‐Jun, although not required for Schwann cell development, is therefore central to the reprogramming of myelin and non‐myelin (Remak) Schwann cells to repair cells after injury. In future, the signalling that specifies this cell requires further analysis so that pharmacological tools that boost and maintain the repair Schwann cell phenotype can be developed.

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Author and article information

Contributors

Claire Jacob:

ORCID: http://orcid.org/0000-0001-9567-3950

cjacob@uni-mainz.de

Journal

Journal ID (nlm-ta): Cell Mol Life Sci

Journal ID (iso-abbrev): Cell Mol Life Sci

Title: Cellular and Molecular Life Sciences

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1420-682X

ISSN (Electronic): 1420-9071

Publication date (Electronic): 10 April 2020

Publication date PMC-release: 10 April 2020

Publication date (Print): 2020

Volume: 77

Issue: 20

Pages: 3977-3989

Affiliations

GRID grid.5802.f, ISNI 0000 0001 1941 7111, Faculty of Biology, Institute of Developmental Biology and Neurobiology, , Johannes Gutenberg University, ; Mainz, Germany

Author information

Claire Jacob http://orcid.org/0000-0001-9567-3950

Article

Publisher ID: 3516

DOI: 10.1007/s00018-020-03516-9

PMC ID: 7532964

PubMed ID: 32277262

SO-VID: 2107c1a0-902f-40da-a401-78a547ecbcda

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 4 January 2020

Date revision received : 9 March 2020

Date accepted : 30 March 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001708, International Foundation for Research in Paraplegia;

Award ID: P 174

Award Recipient : Claire Jacob

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ScienceOpen disciplines: Molecular biology

Keywords: schwann cell,plasticity,reprogramming,chromatin remodeling enzymes,transcription factors,signaling pathways,nerve injury and repair,axonal regeneration,remyelination

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ScienceOpen disciplines: Molecular biology

Keywords: schwann cell, plasticity, reprogramming, chromatin remodeling enzymes, transcription factors, signaling pathways, nerve injury and repair, axonal regeneration, remyelination

Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury

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Most cited references 123

Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.

Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.

The repair Schwann cell and its function in regenerating nerves

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