Studies on the Development and Behavior of the Dystrophic Growth Cone, the Hallmark of Regeneration Failure, in an In Vitro Model of the Glial Scar and after Spinal Cord Injury

The Journal of Neuroscience, 2004 · DOI: 10.1523/JNEUROSCI.0994-04.2004 · Published: July 21, 2004

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

After spinal cord injury, a glial scar forms that poses a major impediment to CNS regeneration. In the region of forming scar tissue, the ends of the regenerating axons cease extending and become swollen and distorted into various bizarrely shaped “growth cones” that can remain for years within axon tracts. The researchers developed an in vitro model of the glial scar that mimics the gradient of proteoglycan found in vivo after spinal cord injury. In this model, regenerated axons from adult sensory neurons that extended deeply into the gradient developed bulbous, vacuolated endings that looked remarkably similar to dystrophic endings formed in vivo. Time-lapsemoviesdemonstratedthatdystrophicendingscontinuallysendoutmembraneveilsandendocytoselargemembranevesicles at the leading edge, which were then retrogradely transported to the rear of the “growth cone.” This direction of movement is contrary to membrane dynamics that occur during normal neurite outgrowth.

Study Duration

Not specified

Participants

Adult Sprague Dawley female rats

Evidence Level

In vitro and in vivo study

Key Findings

1
PGs can lead to growth cone dystrophy and that, surprisingly, supposedly sterile dystrophic endings are extraordinarily dynamic.
2
Dystrophic endings in vivo are also quite active, at least for 1 week after injury.
3
Dystrophic endballs have an exaggerated rate of endocytosis and that this process apparently occurs at the peripheral domain of the growth cone may violate the tenets of normal membrane dynamics, resulting in a state that is exceptionally nonconducive for elongation.

Research Summary

The study developed an in vitro assay that mimics the PG gradient phenotype in the glial scar, demonstrating that adult DRGs form dystrophic endings morphologically and behaviorally similar to those in vivo. The research showed that dystrophic endballs are dynamic both in vitro and in vivo, suggesting they may be more capable of regeneration than previously thought. The dynamic behavior of dystrophic endballs is closely associated with the formation of large membrane vesicles, and these vesicles may be part of a turnover mechanism that allows for endocytosis of membrane.

Practical Implications

Therapeutic Targets

Identifying signaling cascades active in the trauma-induced dystrophic state may reveal potential therapeutic paths.

Harnessing Growth Potential

Learning how to properly harness the growth potential of dystrophic growth cones while modifying the negative aspects of scarring may lead to successful regeneration across the scar.

Understanding Regeneration Failure

The distribution of inhibitory matrices in a gradient transforms the growth cone into a state that is apparently incapable of freeing itself from the lesion environment.

Study Limitations

1
The study acknowledges that it does not yet know what roles other potential inhibitors, such as semaphorins, ephrins, slits, and other types of proteoglycans, may play in triggering the dystrophic state in vivo.
2
The long-term behavior of dystrophic endings (beyond 1 week post-lesion) could not be accurately assessed in vivo due to technical limitations in delivering dextran without causing additional injury.
3
Variations in inhibitory potency between different lots of aggrecan required the use of relatively high concentrations to stabilize the aggrecan effect.

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