Hydrogen peroxide induced by nerve injury promotes axon regeneration via connective tissue growth factor

Acta Neuropathologica Communications

Research

Florigio Lista¹  Silvia Fillo¹  Chiara Romualdi²  Gabriele Sales²  Giorgia D’Este³  Marco Stazi³  Marco Pirazzini⁴  Michela Rigoni⁴  Aram Megighian⁵  Samuele Negro⁶  Toma Tebaldi⁷  Andrew P. Tosolini⁸  James N. Sleigh⁹  Giampietro Schiavo⁹  Gabriella Viero^1,10  Fabio Lauria^1,10  Chiara M. Mazzanti^1,11  Francesca Lessi^1,11 

[1] Center of Medical and Veterinary Research of the Ministry of Defence, 00184, Rome, Italy;Department of Biology, University of Padua, 35131, Padua, Italy;Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy;Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy;Myology Center (CIR-Myo), University of Padua, 35129, Padua, Italy;Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy;Padua Neuroscience Center, University of Padua, 35131, Padua, Italy;Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy;U.O.C. Clinica Neurologica, Azienda Ospedale, University of Padua, 35128, Padua, Italy;Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123, Povo, Italy;Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, 06520, New Haven, CT, USA;Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK;UCL Queen Square Motor Neuron Disease Centre, University College London, WC1N 3BG, London, UK;Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK;UCL Queen Square Motor Neuron Disease Centre, University College London, WC1N 3BG, London, UK;UK Dementia Research Institute, University College London, WC1E 6BT, London, UK;Institute of Biophysics, CNR Unit at Trento, 38123, Povo, Italy;Laboratory of Genomics, Pisa Science Foundation, 56017, San Giuliano Terme, Italy;

关键词: Connective tissue growth factor;    Hydrogen peroxide;    Nerve regeneration;    Neuromuscular junction;    Schwann cells;    Yes-associated protein;   

DOI  :  10.1186/s40478-022-01495-5

 received in 2022-08-26, accepted in 2022-12-12,  发布年份 2022

来源: Springer

【 摘 要 】

Regeneration of the neuromuscular junction (NMJ) leverages on extensive exchange of factors released from motor axon terminals (MATs), muscle fibers and perisynaptic Schwann cells (PSCs), among which hydrogen peroxide (H2O2) is a major pro-regenerative signal. To identify critical determinants of NMJ remodeling in response to injury, we performed temporal transcriptional profiling of NMJs from 2 month-old mice during MAT degeneration/regeneration, and cross-referenced the differentially expressed genes with those elicited by H2O2 in SCs. We identified an enrichment in extracellular matrix (ECM) transcripts, including Connective Tissue Growth Factor (Ctgf), which is usually expressed during development. We discovered that Ctgf levels are increased in a Yes-associated protein (YAP)-dependent fashion in response to rapid, local H2O2 signaling generated by stressed mitochondria in the injured sciatic nerve, a finding highlighting the importance of signals triggered by mechanical force to motor nerve repair. Through sequestration of Ctgf or inactivation of H2O2, we delayed the recovery of neuromuscular function by impairing SC migration and, in turn, axon-oriented re-growth. These data indicate that H2O2 and its downstream effector Ctgf are pro-regenerative factors that enable axonal growth, and reveal a striking ECM remodeling process during nerve regeneration upon local H2O2 signaling. Our study identifies key transcriptomic changes at the regenerating NMJ, providing a rich source of pro-regenerative factors with potential for alleviating the consequences of peripheral nerve injuries.

【 授权许可】

CC BY   
© The Author(s) 2022

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