Functional Axonal Regeneration through Astrocytic Scar Genetically Modified to Digest Chondroitin Sulfate Proteoglycans

The Journal of Neuroscience, 2007 · DOI: 10.1523/JNEUROSCI.5176-06.2007 · Published: February 28, 2007

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Following CNS injury, axons often fail to regenerate due to inhibitory molecules like chondroitin sulfate proteoglycans (CSPGs). This study explores the role of CSPGs in limiting regeneration by expressing a CSPG-degrading enzyme, chondroitinase ABC (ChABC), in astrocytes of transgenic mice. The researchers found that in these transgenic mice, corticospinal axons extended within the lesion site after a dorsal hemisection, but this did not lead to significant motor function recovery. However, sensory axon regeneration was significantly improved after a dorsal rhizotomy. These findings suggest that CSPGs play a spatially distinct role from myelin inhibitors and that therapies combining different approaches may be more effective for CNS injuries.

Study Duration

4 weeks, and acute vs chronic groups at 3 and 21 days

Participants

Transgenic mice and wild-type littermates

Evidence Level

Level II: Transgenic animal study

Key Findings

1
Transgenic expression of ChABC allows CST axons to enter scar tissue after dorsal hemisection, but does not significantly improve motor function recovery.
2
Transgenic expression of ChABC promotes regeneration of sensory neurons after dorsal rhizotomy.
3
Transgenic expression of ChABC restores nociceptive function and cutaneous mechanosensation after dorsal rhizotomy.

Research Summary

This study used transgenic mice expressing chondroitinase ABC (ChABC) to investigate the role of chondroitin sulfate proteoglycans (CSPGs) in limiting axonal regeneration after CNS injury. The researchers found that while ChABC expression allowed corticospinal axons to enter the lesion site after dorsal hemisection, it did not significantly improve motor function. However, sensory axon regeneration and functional recovery were observed after dorsal rhizotomy in the transgenic mice. These findings suggest that CSPGs have a spatially distinct role from myelin inhibitors, and combination therapies may be more advantageous for CNS injuries, emphasizing the importance of CSPG removal for axonal growth in areas undergoing reactive astrogliosis.

Practical Implications

Combination Therapies

Combining CSPG removal with myelin-associated inhibitor strategies may be more effective for CNS injury recovery.

Targeted Drug Delivery

The spatial distribution of ChABC action is crucial; widespread CSPG removal may be necessary for long-distance axonal growth and motor recovery.

Therapeutic Target for Avulsion Injuries

ChABC-dependent growth within scarred areas may be of functional benefit under different circumstances, such as dorsal root avulsion injuries.

Study Limitations

1
The lack of recovery after dorsal hemisection might be a consequence of the nature and severity of the lesion.
2
ChABC expression and subsequent CSPG digestion in this study is limited to a restricted penumbra of tissue at the lesion site and therefore cannot influence distal regions of the nervous system.
3
The early restoration of sensory function in the chronic Tg-ChABC:3 and Tg-ChABC:4 mice does not rule out the possibility that transgenic ChABC expression might enhance intraspinal reorganization of intact primary afferent terminals from adjacent spared dorsal roots.

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