Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling

Francesco Virgiliis, Thomas H. Hutson, Ilaria Palmisano, Sarah Amachree, Jian Miao, Luming Zhou, Rositsa Todorova, Richard Thompson, Matt C. Danzi, Vance P. Lemmon, John L. Bixby, Ilka Wittig, Ajay M. Shah and Simone Giovanni ()
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Francesco Virgiliis: Imperial College London
Thomas H. Hutson: Imperial College London
Ilaria Palmisano: Imperial College London
Sarah Amachree: Imperial College London
Jian Miao: Imperial College London
Luming Zhou: Imperial College London
Rositsa Todorova: Imperial College London
Richard Thompson: King’s College London
Matt C. Danzi: University of Miami
Vance P. Lemmon: University of Miami
John L. Bixby: University of Miami
Ilka Wittig: Goethe University
Ajay M. Shah: King’s College London
Simone Giovanni: Imperial College London

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site. Mechanistically, we established that enriched conditioning relies on the unique neuronal intrinsic signaling axis PKC-STAT3-NADPH oxidase 2 (NOX2), enhancing redox signaling as shown by redox proteomics in DRG. Finally, NOX2 conditional deletion or overexpression respectively blocked or phenocopied enriched conditioning-dependent axon regeneration after SCI leading to improved functional recovery. These studies provide a paradigm that drives the regenerative ability of sensory neurons offering a potential redox-dependent regenerative model for mechanistic and therapeutic discoveries.

Date: 2020
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DOI: 10.1038/s41467-020-20179-z

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