Assessment of Glial Scar, Tissue Sparing, Behavioral Recovery and Axonal Regeneration following Acute Transplantation of Genetically Modified Human Umbilical Cord Blood Cells in a Rat Model of Spinal Cord Contusion

PLoS One. 2016 Mar 22;11(3):e0151745. doi: 10.1371/journal.pone.0151745. eCollection 2016.

Abstract

Objective and methods: This study investigated the potential for protective effects of human umbilical cord blood mononuclear cells (UCB-MCs) genetically modified with the VEGF and GNDF genes on contusion spinal cord injury (SCI) in rats. An adenoviral vector was constructed for targeted delivery of VEGF and GDNF to UCB-MCs. Using a rat contusion SCI 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.

Results: Transplantation of UCB-MCs transduced with adenoviral vectors expressing VEGF and GDNF at the site of SCI induced tissue sparing, behavioral recovery and axonal regeneration comparing to the other constructs tested. The adenovirus encoding VEGF and GDNF for transduction of UCB-MCs was shown to be an effective and stable vehicle for these cells in vivo following the transplantation into the contused spinal cord.

Conclusion: Our results show that a gene delivery using UCB-MCs-expressing VEGF and GNDF genes improved both structural and functional parameters after SCI. Further histological and behavioral studies, especially at later time points, in animals with SCI after transplantation of genetically modified UCB-MCs (overexpressing VEGF and GDNF genes) will provide additional insight into therapeutic potential of such cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology
  • Cicatrix
  • Disease Models, Animal
  • Female
  • Fetal Blood / cytology
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Glial Cell Line-Derived Neurotrophic Factor / biosynthesis
  • Glial Cell Line-Derived Neurotrophic Factor / genetics*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / transplantation*
  • Male
  • Motor Activity / physiology
  • Nerve Regeneration / physiology*
  • Neuroglia / pathology
  • RNA, Messenger / biosynthesis
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Recovery of Function / physiology
  • Spinal Cord
  • Spinal Cord Injuries / physiopathology
  • Spinal Cord Injuries / therapy*
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • GDNF protein, human
  • Glial Cell Line-Derived Neurotrophic Factor
  • RNA, Messenger
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins

Grants and funding

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.