Transplantation of genetically modified cells carrying a transgene has a greater stimulating effect on the regeneration of post-traumatic central nervous system.
During spinal cord injury, the extensive area adjacent to the epicenter of the injury gets involved in the pathological process. As such, in order to achieve complete therapeutic action, the therapeutic gene must be delivered not only to the epicenter of traumatic injury but also to the surrounding areas distant from the epicenter of injury.
Two transgenes such as vascular endothelial growth factor (VEGF) and glial cell-derived neurotrophic factor (GDNF) proved to be powerful factors in the maintenance of viability of a number of cell different populations in the spinal cord, including the motor neurons.
VEGF stimulates neurogenesis and axonal growth as well as the rapid reproduction of astrocytes, neural stem, and Schwann cells. GDNF reduces apoptosis and tissue degeneration, supports expression of neurofilament protein, calcitonin gene-related peptide (CGRP) and growth associated protein 43.
For this study, researchers of Kazan Federal University and Kazan State Medical University chose human umbilical cord blood mononuclear cells (UCB-MCs), easy to produce and safe, with low immunogenicity and the potential to increase neuroregeneration, transduced with these two genes VEGF and GDNF.
"Considering the action of VEGF and GDNF through different receptors and pathways, we hypothesized that the simultaneous delivery of these two therapeutic genes would promote synergistic neuroprotective effects.
Thus, using a rat contusion spinal cord injury model we examined the efficacy of the construct on tissue sparing, glial scar severity, the extent of axonal regeneration, recovery of motor function, and analyzed the expression of the recombinant genes VEGF and GNDF in vitro and in vivo" comments one of the authors Yana Mukhamedshina.
The results obtained show that the adenoviral vectors encoding VEGF and GDNF, used to transduce UCB-MCs, were shown to be an effective and stable in these cells following transplantation.
The construct managed to increase tissue sparing and numbers of spared/regenerated axons, reduce glial scar formation and promote behavioral recovery when transplanted immediately after a rat contusion spinal cord injury. Researchers conclude that genetically modified human umbilical cord blood cells are a promising strategy for enhancing posttraumatic spinal cord regeneration.
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The study was supported by grants 15-04-07527 (A.A. Rizvanov) and 14-04-31246 (Y.O.Mukhamedshina) from Russian Foundation for Basic Research. Y.O. Mukhamedshina was supported by a Presidential Grant for government support of young scientists (PhD) from the Russian Federation (MK-4020.2015.7). This work was performed in accordance with Program of Competitive Growth of
Kazan Federal University and a subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities. Some of the experiments were conducted using equipment at the Interdisciplinary Center for Collective Use of Kazan Federal University supported by Ministry of Education of Russia (ID RFMEFI59414X0003), Interdisciplinary Center for Analytical Microscopy, and Pharmaceutical Research and Education Center, Kazan (Volga Region) Federal University, Kazan, Russia.
Journal
PLoS ONE