IGF-I gene delivery promotes corticospinal neuronal survival but not regeneration after adult CNS injury

Abstract

An unmet challenge of spinal cord injury research is the identification of mechanisms that promote regeneration of corticospinal motor axons. Recently it was reported that IGF-I promotes corticospinal axon growth during nervous system development. We therefore investigated whether IGF-I also promotes regeneration or survival of adult lesioned corticospinal neurons. Adult Fischer 344 rats underwent C3 dorsal column transections followed by grafts of IGF-I-secreting marrow stromal cell grafts into the lesion cavity. IGF-I secreting cell grafts promoted growth of raphespinal and cerulospinal axons, but not corticospinal axons, into the lesion/graft site. We then examined whether IGF-I-secreting cell grafts promote corticospinal motor neuron survival or axon growth in a subcortical axotomy model. IGF-I expression coupled with infusion of the IGF binding protein inhibitor NBI-31772 significantly prevented corticospinal motor neuron death (93% cell survival compared to 49% in controls, P < 0.05), but did not promote corticospinal axon regeneration. Coincident with observed effects of IGF-I on corticospinal survival but not growth, expression of IGF-I receptors was restricted to the somal compartment and not the axon of adult corticospinal motor neurons. Thus, whereas IGF-I influences corticospinal axonal growth during development, its application to sites of adult spinal cord injury or subcortical axotomy fails to promote corticospinal axonal regeneration under conditions that are sufficient to prevent corticospinal cell death and promote the growth of other supraspinal axons. We conclude that developmental patterns of growth factor responsiveness are not simply recapitulated after adult injury, potentially due to post-natal shifts in patterns of IGF-I receptor expression.