Motor Axonal Regeneration after Partial and Complete Spinal Cord Transection

Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2012; 32(24):8208-18. DOI: 10.1523/JNEUROSCI.0308-12.2012
Source: PubMed


We subjected rats to either partial midcervical or complete upper thoracic spinal cord transections and examined whether combinatorial treatments support motor axonal regeneration into and beyond the lesion. Subjects received cAMP injections into brainstem reticular motor neurons to stimulate their endogenous growth state, bone marrow stromal cell grafts in lesion sites to provide permissive matrices for axonal growth, and brain-derived neurotrophic factor gradients beyond the lesion to stimulate distal growth of motor axons. Findings were compared with several control groups. Combinatorial treatment generated motor axon regeneration beyond both C5 hemisection and T3 complete transection sites. Yet despite formation of synapses with neurons below the lesion, motor outcomes worsened after partial cervical lesions and spasticity worsened after complete transection. These findings highlight the complexity of spinal cord repair and the need for additional control and shaping of axonal regeneration.

    • "This may be addressed by limiting the expression of BDNF inside the lesion to a defined time period, e.g. via regulated transgene expression [50] and/or delivery of neurotrophic factors in the spinal cord distal to the lesion by direct injection of growth factors [51] or viral vectors expressing trophic factors [48] [52] [53]. Thereby, a gradient of growth factor with the highest concentration in the distal host parenchyma can be generated. "
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    ABSTRACT: Despite recent progress in enhancing axonal growth in the injured spinal cord, the guidance of regenerating axons across an extended lesion site remains a major challenge. To determine whether regenerating axons can be guided in rostrocaudal direction, we implanted 2 mm long alginate-based anisotropic capillary hydrogels seeded with bone marrow stromal cells (BMSCs) expressing brain-derived neurotrophic factor (BDNF) or green fluorescent protein (GFP) as control into a C5 hemisection lesion of the rat spinal cord. Four weeks post-lesion, numerous BMSCs survived inside the scaffold channels, accompanied by macrophages, Schwann cells and blood vessels. Quantification of axons growing into channels demonstrated 3 - 4 times more axons in hydrogels seeded with BMSCs expressing BDNF (BMSC-BDNF) compared to control cells. The number of anterogradely traced axons extending through the entire length of the scaffold was also significantly higher in scaffolds with BMSC-BDNF. Increasing the channel diameters from 41 μm to 64 μm did not lead to significant differences in the number of regenerating axons. Lesions filled with BMSC-BDNF without hydrogels exhibited a random axon orientation, whereas axons were oriented parallel to the hydrogel channel walls. Thus, alginate-based scaffolds with an anisotropic capillary structure are able to physically guide regenerating axons.
    No preview · Article · Sep 2015 · Acta biomaterialia
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    • "Spinal cord injury (SCI) with complete axonal transection precludes any degree of sensorimotor or autonomous functional recovery [1], [2]. In contrast, neurological and consecutively functional recovery is consistently observed in individuals with incomplete SCI, reflected by conversion in the American Spinal Injury Association Impairment Scale and by gains in respective functional assessments, such as the Spinal Cord Independence Measure and the Walking Index for Spinal Cord Injury [3]–[5]. "
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    ABSTRACT: After spinal cord injury, transected axons fail to regenerate, yet significant, spontaneous functional improvement can be observed over time. Distinct central nervous system regions retain the capacity to generate new neurons and glia from an endogenous pool of progenitor cells and to compensate neural cell loss following certain lesions. The aim of the present study was to investigate whether endogenous cell replacement (neurogenesis or gliogenesis) in the brain (subventricular zone, SVZ; corpus callosum, CC; hippocampus, HC; and motor cortex, MC) or cervical spinal cord might represent a structural correlate for spontaneous locomotor recovery after a thoracic spinal cord injury. Adult Fischer 344 rats received severe contusion injuries (200 kDyn) of the mid-thoracic spinal cord using an Infinite Horizon Impactor. Uninjured rats served as controls. From 4 to 14 days post-injury, both groups received injections of bromodeoxyuridine (BrdU) to label dividing cells. Over the course of six weeks post-injury, spontaneous recovery of locomotor function occurred. Survival of newly generated cells was unaltered in the SVZ, HC, CC, and the MC. Neurogenesis, as determined by identification and quantification of doublecortin immunoreactive neuroblasts or BrdU/neuronal nuclear antigen double positive newly generated neurons, was not present in non-neurogenic regions (MC, CC, and cervical spinal cord) and unaltered in neurogenic regions (dentate gyrus and SVZ) of the brain. The lack of neuronal replacement in the brain and spinal cord after spinal cord injury precludes any relevance for spontaneous recovery of locomotor function. Gliogenesis was increased in the cervical spinal cord remote from the injury site, however, is unlikely to contribute to functional improvement.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Self-complementary adeno-associated viral vectors (scAAV) were generated as described by Lu et al. (11). In order to attract regenerative growth out of the graft into the caudal spinal cord, BDNF, and NT-3 (and GFP as control) transfected scAAV vectors (1.3 μl/site) were injected 1.25, 2.5, and 4 mm caudal to the lesion on the side ipsilateral to the lesion through pulled glass capillaries using a Picospritzer II similar to Lu et al. (11). "
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    ABSTRACT: We have recently reported that rats with complete thoracic spinal cord injury (SCI) that received a combinatorial treatment, including viral brain-derived neurotrophic factor (BDNF) delivery in the spinal cord, not only showed enhanced axonal regeneration, but also deterioration of hind-limb motor function. By demonstrating that BDNF over-expression can trigger spasticity-like symptoms in a rat model of sacral SCI, we proposed a causal relationship between the observed spasticity-like symptoms (i.e., resistance to passive range of motion) and the over-expression of BDNF. The current study was originally designed to evaluate a comparable combined treatment for cervical SCI in the rat to improve motor recovery. Once again we found similar signs of spasticity involving clenching of the paws and wrist flexion. This finding changed the focus of the study and, we then explored whether this spasticity-like symptom is directly related to the over-expression of BDNF by administering a BDNF antagonist. Using electromyographic measurements we showed that this treatment gradually diminished the resistance to overcome forelimb flexion in an acute experiment. Thus, we conclude that neuro-excitatory effects of chronic BDNF delivery together with diminished descending control after SCI can result in adverse effects.
    Full-text · Article · Nov 2013 · Frontiers in Neurology
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