Schwann Cell Transplantation Improves Reticulospinal Axon Growth and Forelimb Strength after Severe Cervical Spinal Cord Contusion

Abstract

Schwann cell (SC) implantation alone has been shown to promote the growth of propriospinal and sensory axons, but not long-tract descending axons, after thoracic spinal cord injury (SCI). In the current study, we examined if an axotomy close to the cell body of origin (so as to enhance the intrinsic growth response) could permit supraspinal axons to grow onto SC grafts. Adult female Fischer rats received a severe (C5) cervical contusion (1.1 mm displacement, 3 KDyn). At 1 week postinjury, 2 million SCs ex vivo transduced with lentiviral vector encoding enhanced green fluorescent protein (EGFP) were implanted within media into the injury epicenter; injury-only animals served as controls. Animals were tested weekly using the BBB score for 7 weeks postimplantation and received at end point tests for upper body strength: self-supported forelimb hanging, forearm grip force, and the incline plane. Following behavioral assessment, animals were anterogradely traced bilaterally from the reticular formation using BDA-Texas Red. Stereological quantification revealed a twofold increase in the numbers of preserved NeuN+ neurons rostral and caudal to the injury/graft site in SC implanted animals, corroborating previous reports of their neuroprotective efficacy. Examination of labeled reticulospinal axon growth revealed that while rarely an axon was present within the lesion site of injury-only controls, numerous reticulospinal axons had penetrated the SC implant/lesion milieu. This has not been observed following implantation of SCs alone into the injured thoracic spinal cord. Significant behavioral improvements over injury-only controls in upper limb strength, including an enhanced grip strength (a 296% increase) and an increased self-supported forelimb hanging, accompanied SC-mediated neuroprotection and reticulospinal axon growth. The current study further supports the neuroprotective efficacy of SC implants after SCI and demonstrates that SCs alone are capable of supporting modest supraspinal axon growth when the site of axon injury is closer to the cell body of the axotomized neuron.Key words: Axon regeneration; Axotomy; Cell body response; Intrinsic; Neuron; Neuroprotection; Supraspinal INTRODUCTIONapies aimed at the promotion of axon growth (59,86,134,142), remyelination (17,22,64,71,73) or neuroreplacement (37,126,137,150). Among the most successful The spinal cord is a critical communication pathway for facilitating the bilateral transmission of sensory and strategies for SCI repair are those that involve exogenous cell implantation (105,106), often when combined motor modalities between the brain and the periphery. Injury to this structure often results in permanent paralywith additional pharmacological or molecular therapies (105,106). sis and lifelong disability (92). Treatments to target spinal cord injury (SCI) in experimental models have fo-The implantation of peripheral nerve grafts into the spinal cord was first used to demonstrate that, contrary cused on (i) protecting the spinal cord from secondary injury t...

Alterations of action potentials and the localization of Nav1.6 sodium channels in spared axons after hemisection injury of the spinal cord in adult rats

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