Axonal Regeneration and Functional Recovery after Complete Spinal Cord Transection in Rats by Delayed Treatment with Transplants and Neurotrophins

Abstract

Little axonal regeneration occurs after spinal cord injury in adult mammals. Regrowth of mature CNS axons can be induced, however, by altering the intrinsic capacity of the neurons for growth or by providing a permissive environment at the injury site. Fetal spinal cord transplants and neurotrophins were used to influence axonal regeneration in the adult rat after complete spinal cord transection at a midthoracic level. Transplants were placed into the lesion cavity either immediately after transection (acute injury) or after a 2-4 week delay (delayed or chronic transplants), and either vehicle or neurotrophic factors were administered exogenously via an implanted minipump. Host axons grew into the transplant in all groups. Surprisingly, regeneration from supraspinal pathways and recovery of motor function were dramatically increased when transplants and neurotrophins were delayed until 2-4 weeks after transection rather than applied acutely. Axonal growth back into the spinal cord below the lesion and transplants was seen only in the presence of neurotrophic factors. Furthermore, the restoration of anatomical connections across the injury site was associated with recovery of function with animals exhibiting plantar foot placement and weight-supported stepping. These findings suggest that the opportunity for intervention after spinal cord injury may be greater than originally envisioned and that CNS neurons with long-standing injuries can reinitiate growth, leading to improvement in motor function.

Part I: Minicircle vector technology limits DNA size restrictions on ex vivo gene delivery using nanoparticle vectors: Overcoming a translational barrier in neural stem cell therapy

“…Neurorestoration requires long-term therapeutic intervention [50][51][52] so from a clinical perspective, achieving sustained gene/protein expression can significantly reduce costs and time by reducing the need for repeat administration of therapeutic proteins/cells. Notably, a sustained yet tapered profile of therapeutic biomolecule expression may be beneficial as it mirrors the temporal pattern of molecular expression profiles that are associated with regenerative processes in pathology sites [22].…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…275 Analagous to the peripheral nerve environment, axons grow readily into grafts of fetal tissue, but emerge distally in a more limited fashion, a limitation that may be overcome by concomitant administration of neurotrophic factors. 155,276 Transplantation of fetal spinal tissue has been tested clinically in the United States in patients with progressive post-traumatic syringomyelia, and preliminary reports suggest that this treatment is safe, 277,278 although complete reports have not been published. Since the use of fetal tissue entails ethical challenges, it may need to be proven superior to other biological bridges in order to assume the role of a preferred clinical bridging intervention.…”

Repair of spinal cord injuries: where are we, where are we going?

“…Direct application of puri®ed neurotrophins has been successful in inducing axon regeneration in the cord by itself, 28 or larger amounts of regeneration has been achieved by combining neurotrophin treatment with either anti Nogo antibodies or embryonic grafts. 3,29 The most successful neurotrophin has been NT-3, for which there are receptors on corticospinal and on large sensory axons, and corticospinal axons regenerate in large numbers past grafts of NT-3 secreting ®broblasts. 30 Nerve growth factor also promotes regeneration, but receptors for it are prominent on small pain axons, so hyperalgesia can be caused by its presence in excess.…”

“…This tissue is also permissive to axon regeneration, and implantation into the injured cord produces some return of function, which is much greater if neurotrophis are given at the same time. 3 Exactly how the grafts exert their e ect is not completely clear. Host axons regenerate into embryonic grafts and appear to form connections with the neurones in the graft, but only in the presence of exogenous neurotrophins will axons regenerate through the grafts and back into the host cord (Figure 1d).…”