Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord

eLife, 2021 · DOI: https://doi.org/10.7554/eLife.63050 · Published: May 4, 2021

Spinal Cord Injury Neurology Regenerative Medicine & Stem Cells

Simple Explanation

This study investigates why damaged nerve fibers from the body (sensory axons) fail to regrow into the spinal cord after injury. Researchers explored whether certain substances that inhibit nerve growth, called myelin inhibitors and CSPGs, are the main reason for this regrowth failure. The findings suggest that while these inhibitors play a role, other, more potent factors prevent nerve regeneration unless the nerves are strongly stimulated to grow.

Study Duration

2-4 weeks

Participants

Mice (Rtn4/Mag/Omg triple knockout, wildtype C57BL/6J)

Evidence Level

Not specified

Key Findings

1
Genetic deletion of myelin inhibitors (Nogo, MAG, OMgp) alone elicits little regeneration across the dorsal root entry zone (DREZ).
2
Additional removal of CSPGs in mice lacking myelin inhibitors only modestly enhances regeneration, even after a conditioning lesion.
3
Removal of myelin inhibitors markedly enhances intraspinal regeneration of glial cell line-derived neurotrophic factor (GDNF)-stimulated DR axons.

Research Summary

The study investigates dorsal root (DR) regeneration after injury, focusing on the roles of myelin inhibitors and chondroitin sulfate proteoglycans (CSPGs). It finds that co-eliminating myelin inhibitors and CSPGs only slightly increases regeneration across the DR entry zone (DREZ), even after a conditioning lesion, suggesting other inhibitory mechanisms are at play. However, the absence of these inhibitors markedly enhances regeneration of GDNF-stimulated axons, indicating that sufficient elevation of intrinsic growth capacity is crucial for overcoming the DREZ barrier.

Practical Implications

Therapeutic Target Identification

Identifies that myelin inhibitors and CSPGs are not the primary inhibitors of DR regeneration, suggesting other targets should be investigated.

Combinatorial Therapies

Highlights the potential for combining treatments that enhance intrinsic growth capacity with therapies that target myelin inhibitors and CSPGs.

Refining Regeneration Strategies

Suggests that therapeutic strategies should focus on identifying and overcoming the myelin/CSPG-independent mechanisms that potently restrain axons at the DREZ.

Study Limitations

1
The study may have limitations related to the specificity of AAV2-GFP for labeling all DR axons.
2
The reliance on a DR crush model, which can be difficult to perform completely, may introduce variability in the results.
3
The study focuses primarily on proprioceptive and mechanoreceptive axons, and the findings may not be generalizable to other types of sensory axons.

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