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

Acta Neuropathol Commun. 2022 Dec 25;10(1):189. doi: 10.1186/s40478-022-01495-5.

Samuele Negro ^# ¹ ², Fabio Lauria ^# ³, Marco Stazi ^# ¹, Toma Tebaldi ⁴ ⁵, Giorgia D'Este ¹, Marco Pirazzini ¹ ⁶, Aram Megighian ¹ ⁷, Francesca Lessi ⁸, Chiara M Mazzanti ⁸, Gabriele Sales ⁹, Chiara Romualdi ⁹, Silvia Fillo ¹⁰, Florigio Lista ¹⁰, James N Sleigh ¹¹ ¹² ¹³, Andrew P Tosolini ¹¹ ¹², Giampietro Schiavo ¹¹ ¹² ¹³, Gabriella Viero ³, Michela Rigoni ¹⁴ ¹⁵

Affiliations

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

PMID: 36567321 DOI: 10.1186/s40478-022-01495-5

Abstract

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.

Keywords

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

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HY-134957

VT107

99.91%, pan-TEAD Auto-Palmitoylation Inhibitor

YAP

Cancer

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