IGF-I Gene Delivery Promotes Corticospinal Neuronal Survival But Not Regeneration After Adult CNS Injury

Exp Neurol, 2009 · DOI: 10.1016/j.expneurol.2008.09.014 · Published: January 1, 2009

Spinal Cord Injury Regenerative Medicine Genetics

Simple Explanation

This study investigates whether Insulin-like Growth Factor I (IGF-I) can promote the regeneration of corticospinal motor axons after spinal cord injury in adult rats. The researchers delivered IGF-I to the injury site using marrow stromal cell grafts. The results showed that while IGF-I promoted the growth of other types of axons (raphespinal and coerulospinal), it did not stimulate the regeneration of corticospinal axons into the lesion site. However, IGF-I did improve the survival of corticospinal motor neurons after a different type of injury (subcortical axotomy). The researchers suggest that the lack of corticospinal axon regeneration might be because the IGF-I receptor is mainly found on the cell body (soma) of the corticospinal neurons and not on their axons in adults. This difference in receptor location compared to development may explain why IGF-I doesn't promote axon regeneration in adults.

Study Duration

4 Weeks

Participants

Adult Fischer 344 rats

Evidence Level

Not specified

Key Findings

1
IGF-I secreting cell grafts promoted growth of raphespinal and coerulospinal axons into the lesion/graft site after C3 dorsal column transections in adult rats.
2
IGF-I expression coupled with the IGF binding protein inhibitor NBI-31772 significantly prevented corticospinal motor neuron death after subcortical axotomy.
3
IGF-I receptors were restricted to the somal compartment and not the axon of adult corticospinal motor neurons, potentially explaining the differential effects on survival versus regeneration.

Research Summary

This study investigated the potential of IGF-I gene delivery to promote corticospinal axon regeneration and neuronal survival after spinal cord injury in adult rats. IGF-I secreting cell grafts were used to deliver IGF-I to the injury site. The results demonstrated that IGF-I promoted the growth of raphespinal and coerulospinal axons but not corticospinal axons into the lesion site. However, IGF-I did promote the survival of corticospinal motor neurons after subcortical axotomy, especially when combined with an IGF binding protein inhibitor. The study suggests that the lack of corticospinal axon regeneration may be due to the absence of IGF-I receptors on corticospinal axons in adults, indicating a developmental shift in growth factor responsiveness.

Practical Implications

Therapeutic strategies for spinal cord injury

The study suggests that IGF-I alone may not be sufficient to promote corticospinal axon regeneration after spinal cord injury. Future therapies may need to combine IGF-I with other factors that promote axon growth or target the IGF-I receptor specifically to the axon.

Understanding developmental changes

The findings highlight the importance of understanding developmental changes in growth factor receptor expression. What works to promote axon growth during development may not work in adults due to changes in receptor location and function.

Combinatorial approaches

The study indicates that combinatorial approaches, such as combining IGF-I with IGF binding protein inhibitors, may be necessary to achieve desired therapeutic outcomes in spinal cord injury.

Study Limitations

1
The study only examined the effects of IGF-I in a specific rat model of spinal cord injury.
2
The levels of IGF-I expression achieved may not have been sufficient to elicit corticospinal axon regeneration, although they were sufficient to promote the growth of other axon types.
3
The study did not investigate the intracellular signaling pathways involved in IGF-I's effects on corticospinal neurons.

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