Cellular Delivery of Neurotrophin-3 Promotes Corticospinal Axonal Growth and Partial Functional Recovery after Spinal Cord Injury

Abstract

The injured adult mammalian spinal cord shows little spontaneous recovery after injury. In the present study, the contribution of projections in the dorsal half of the spinal cord to functional loss after adult spinal cord injury was examined, together with the effects of transgenic cellular delivery of neurotrophin-3 (NT-3) on morphological and functional disturbances. Adult rats underwent bilateral dorsal column spinal cord lesions that remove the dorsal corticospinal projections or underwent more extensive resections of the entire dorsal spinal cord bilaterally that remove corticospinal, rubrospinal, and cerulospinal projections. Long-lasting functional deficits were observed on a motor grid task requiring detailed integration of sensorimotor skills, but only in animals with dorsal hemisection lesions as opposed to dorsal column lesions. Syngenic primary rat fibroblasts genetically modified to produce NT-3 were then grafted to acute spinal cord dorsal hemisection lesion cavities. Up to 3 months later, significant partial functional recovery occurred in NT-3-grafted animals together with a significant increase in corticospinal axon growth at and distal to the injury site. These findings indicate that (1) several spinal pathways contribute to loss of motor function after spinal cord injury, (2) NT-3 is a neurotrophic factor for the injured corticospinal projection, and (3) functional deficits are partially ameliorated by local cellular delivery of NT-3. Lesions of the corticospinal projection may be necessary, but insufficient in isolation, to cause sensorimotor dysfunction after spinal cord injury in the rat.

Cotransplant of neural stem cells and NT-3 gene modified Schwann cells promote the recovery of transected spinal cord injury

“…[7][8][9] Neurotropin-3 (NT-3) is one of the important neurotrophic factors. It can prevent atrophy of mature CNS neurons, and promote corticospinal tract axonal regeneration and recovery of hindlimb's function in spinal cord injured animal [10][11][12][13][14][15] and Hapner et al 16 had indicated that NT-3 could upregulate the TrkC expression of NSCs and promote for them to differentiate into neurons.…”

Neurotrophin‐3 released from implant of tissue‐engineered fibroin scaffolds inhibits inflammation, enhances nerve fiber regeneration, and improves motor function in canine spinal cord injury

“…Collateral axonal sprouting coming from the contralateral corticospinal tract may play a role in motor improvement 51, 52. It is speculated that increased in local NT‐3 level may help axonal sprouting as well as strengthen the motor neurons (L3‐S4) to the sciatic nerve.…”

International spinal research trust research strategy. III: A discussion document

“…In addition to the lack of inhibitory molecules, it is proposed that peripheral nerve grafts support CNS axon regeneration by the secretion of trophic factors. Many studies have shown that growth factors upregulate RAGs and enhance regenerative axon growth, [22][23][24] and genetically modifying transplants to overexpress neurotrophic factors might enhance these effects further. Thus, an effective combination that enhances positive factors and reduces negative ones is an attractive goal for current research.…”