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

Nature Communications, 2020 · DOI: https://doi.org/10.1038/s41467-020-20179-z · Published: December 22, 2020

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Following a spinal cord injury (SCI) in the adult mammalian central nervous system (CNS), axon regeneration is severely limited leading to permanent impairment of sensory and motor function. The regenerative potential of DRG neurons after a peripheral nerve injury or a SCI is enhanced by a prior injury of the peripheral axon: this phenomenon is known as the conditioning lesion. We developed a superior regenerative paradigm by combining EE with SNA (conditioning lesion) before a SCI.

Study Duration

6 weeks

Participants

Mice (WT, NOX2−/−, STAT3fl/fl, LysM-Cre-NOX2−/−, etc.)

Evidence Level

Level 2: Experimental study in animal models

Key Findings

1
Combining environmental enrichment (EE) and sciatic nerve axotomy (SNA) before spinal cord injury (SCI) significantly enhances axon regeneration in dorsal root ganglia (DRG) sensory neurons.
2
Enriched conditioning relies on the PKC-STAT3-NADPH oxidase 2 (NOX2) signaling axis to enhance redox signaling in DRG neurons.
3
Conditional deletion or overexpression of NOX2 blocked or phenocopied enriched conditioning-dependent axon regeneration, respectively, leading to improved functional recovery after SCI.

Research Summary

The study introduces 'enriched conditioning,' a regenerative paradigm combining environmental enrichment (EE) and sciatic nerve axotomy (SNA) prior to spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of DRG sensory neurons, propelling axon growth beyond the spinal injury site. Mechanistically, enriched conditioning relies on the PKC-STAT3-NOX2 signaling axis, enhancing redox signaling.

Practical Implications

Therapeutic Potential

The study suggests a potential redox-dependent regenerative model for therapeutic discoveries related to spinal cord injury.

Enhanced Regeneration Strategies

The enriched conditioning paradigm offers a superior method for promoting axon regeneration compared to traditional conditioning injury approaches.

Targeted Drug Development

The identification of the PKC-STAT3-NOX2 signaling axis provides druggable targets for promoting regeneration and functional recovery after SCI.

Study Limitations

1
The study is primarily conducted in animal models (mice), and the results may not directly translate to humans.
2
The precise mechanisms and contributions of other transcription factors and signaling pathways involved in enriched conditioning require further investigation.
3
The long-term effects and sustainability of the observed functional recovery after SCI need to be evaluated in more extended studies.

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