Abstract
The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.
Highlights
Spinal cord injury (SCI) is a complex condition with multiple cascades of changes such as cell death, inflammatory response, demyelination, as well as impairment of neural connectivity and functions
We confirmed the positive effect of a combination of transgenes encoding vascular endothelial growth factor (VEGF), glial cell neurotrophic factor (GDNF), and nerve cell adhesion molecule (NCAM) on the morpho-functional restoration of the spinal cord after contusion injury in rats [15,16] and pigs [17] models
We suggested that the transduction of UCBMCs with an adenoviral vector carrying NCAM cDNA may have a positive effect on neuroregeneration, and may enhance homing and survivability of the gene-modified umbilical cord blood mononuclear cells (UCBC) after transplantation into ALS mice [30,31]
Summary
Spinal cord injury (SCI) is a complex condition with multiple cascades of changes such as cell death, inflammatory response, demyelination, as well as impairment of neural connectivity and functions. We confirmed the positive effect of a combination of transgenes encoding vascular endothelial growth factor (VEGF), glial cell neurotrophic factor (GDNF), and nerve cell adhesion molecule (NCAM) on the morpho-functional restoration of the spinal cord after contusion injury in rats [15,16] and pigs [17] models. We demonstrated that the EES applied above and below the injury, combined with intrathecal administration of gene modified UCBC overexpressing recombinant VEGF, GDNF, and NCAM, has a cumulative positive effect on remodeling of the spinal cord and promotes locomotor recovery in rodents with SCI [41]. Itnsthaoctwhne)awltheyreaunismedaltso(ncooltleschtobwans)ic bweheareviuorsaeld, etloecctorollpechtysbiaosliocgbiceahl,aavniodrahli,setoleloctgriocpahl ydsaitoalofogriccaol,mapnadrahtiivsteoalongailcyaslisd. ata for comparative analysis
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