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  4. Combined Intrinsic and Extrinsic Neuronal Mechanisms Facilitate Bridging Axonal Regeneration One Year After Spinal Cord Injury

Combined Intrinsic and Extrinsic Neuronal Mechanisms Facilitate Bridging Axonal Regeneration One Year After Spinal Cord Injury

Neuron, 2009 · DOI: 10.1016/j.neuron.2009.09.016 · Published: October 29, 2009

Spinal Cord InjuryRegenerative MedicineNeurology

Simple Explanation

This study investigates methods to promote the regeneration of nerve fibers (axons) in the spinal cord after injury, even long after the initial damage. Researchers found that a combination of treatments can help these fibers regrow across the injury site. The approach involves stimulating the nerve cells themselves to grow and creating a supportive environment around the injury. This was achieved using peripheral nerve conditioning lesions, grafts of marrow stromal cells, and neurotrophic factor gradients. Importantly, the study demonstrates that these treatments can be effective even when started well after the injury, suggesting potential for therapies in chronic spinal cord injury cases. The intraneuronal molecular mechanisms recruited by delayed therapies mirror those of acute injury.

Study Duration
6 weeks to 15 months after SCI
Participants
182 adult Fisher 344 rats
Evidence Level
Not specified

Key Findings

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    Combinatorial therapies (peripheral nerve conditioning lesions, grafts of marrow stromal cells, and NT-3 gradients) promote axonal regeneration into and beyond a mid-cervical lesion site, even when administered 6 weeks to 15 months after SCI.
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    Intraneuronal molecular mechanisms recruited by delayed therapies mirror those of acute injury, including activation of transcriptional activators and regeneration-associated genes.
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    Axonal bridging beyond the lesion occurred only in animals that received combinatorial treatment with CLs, MSC grafts in the lesion cavity, and lenti-NT-3 injections.

Research Summary

This study demonstrates that bridging axonal regeneration can be achieved in the adult CNS even when treatments are initiated at extended delays after spinal cord injury (SCI). Effective regeneration requires modification of both the intrinsic growth state of the neuron (via conditioning lesions) and the creation of a permissive environment at the injury site (cell grafting and growth factor gradients). Delayed conditioning of injured neurons elicits modulation of a broad set of genes remarkably similar to those seen with conditioning lesions placed before central injury, suggesting the recruitment of intrinsic molecular mechanisms that contribute to axonal regeneration.

Practical Implications

Therapeutic Potential

The findings suggest that combinatorial therapies could be developed to promote axonal regeneration in chronic SCI patients, even long after the initial injury.

Targeted Treatments

Treatments should focus on both stimulating intrinsic neuronal growth and modifying the inhibitory environment of the injury site.

Clinical Relevance

Attempting to achieve chronic functional recovery should target cervical level lesions, because potential neuronal targets of regenerating axons can be contacted immediately below the lesion site.

Study Limitations

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