Skip to main content
Article thumbnail
Location of Repository

Ex Vivo VEGF Delivery by Neural Stem Cells Enhances Proliferation of Glial Progenitors, Angiogenesis, and Tissue Sparing after Spinal Cord Injury

By Hyuk Min Kim, Dong Hoon Hwang, Jong Eun Lee, Seung U. Kim and Byung G. Kim

Abstract

The present study was undertaken to examine multifaceted therapeutic effects of vascular endothelial growth factor (VEGF) in a rat spinal cord injury (SCI) model, focusing on its capability to stimulate proliferation of endogenous glial progenitor cells. Neural stem cells (NSCs) can be genetically modified to efficiently transfer therapeutic genes to diseased CNS. We adopted an ex vivo approach using immortalized human NSC line (F3 cells) to achieve stable and robust expression of VEGF in the injured spinal cord. Transplantation of NSCs retrovirally transduced to overexpress VEGF (F3.VEGF cells) at 7 days after contusive SCI markedly elevated the amount of VEGF in the injured spinal cord tissue compared to injection of PBS or F3 cells without VEGF. Concomitantly, phosphorylation of VEGF receptor flk-1 increased in F3.VEGF group. Stereological counting of BrdU+ cells revealed that transplantation of F3.VEGF significantly enhanced cellular proliferation at 2 weeks after SCI. The number of proliferating NG2+ glial progenitor cells (NG2+/BrdU+) was also increased by F3.VEGF. Furthermore, transplantation of F3.VEGF increased the number of early proliferating cells that differentiated into mature oligodendrocytes, but not astrocytes, at 6 weeks after SCI. F3.VEGF treatment also increased the density of blood vessels in the injured spinal cord and enhanced tissue sparing. These anatomical results were accompanied by improved BBB locomotor scores. The multifaceted effects of VEGF on endogenous gliogenesis, angiogenesis, and tissue sparing could be utilized to improve functional outcomes following SCI

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2656622
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Citations

    1. (1995). A sensitive and reliable locomotor rating scale for open field testing in rats.
    2. (2000). Adult Spinal Cord Stem Cells Generate Neurons after Transplantation in the Adult Dentate Gyrus.
    3. (2005). Astrocyte growth effects of vascular endothelial growth factor (VEGF) application to perinatal neocortical explants: receptor mediation and signal transduction pathways.
    4. (2006). Astrocytes derived from glial-restricted precursors promote spinal cord repair.
    5. (2000). Basic fibroblast growth factor (bFGF) enhances functional recovery following severe spinal cord injury to the rat.
    6. (1998). Causes and consequences of natal dispersal in root voles, Microtus oeconomus.
    7. (1999). Cell proliferation and nestin expression in the ependyma of the adult rat spinal cord after injury.
    8. (2005). Cell proliferation and replacement following contusive spinal cord injury.
    9. (1996). Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain.
    10. (1992). Demyelination in spinal cord injury and multiple sclerosis: what can we do to enhance functional recovery?
    11. (2006). Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury.
    12. (1998). Ex vivo nerve growth factor gene transfer to the basal forebrain in presymptomatic middle-aged rats prevents the development of cholinergic neuron atrophy and cognitive impairment during aging.
    13. (2006). Experimental strategies to promote spinal cord regeneration–an integrative perspective.
    14. (1996). Expression of the APC tumor suppressor protein in oligodendroglia.
    15. (2006). Gene therapy: can neural stem cells deliver?
    16. (1999). Genetic engineering for CNS regeneration.
    17. (2008). Genetic modification of neural stem cells.
    18. (2005). Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells.
    19. (2006). Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates.
    20. (2007). Human neural stem cells overexpressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model.
    21. (1996). Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis.
    22. (2006). Neural stem cells may be uniquely suited for combined gene therapy and cell replacement: Evidence from engraftment of Neurotrophin-3-expressing stem cells in hypoxicischemic brain injury.
    23. (2002). Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair.
    24. (2004). New roles for VEGF in nervous tissue–beyond blood vessels.
    25. (2005). NG2 proteoglycan-expressing cells of the adult rat brain: possible involvement in the formation of glial scar astrocytes following stab wound.
    26. (1999). NG2+ glial cells: a novel glial cell population in the adult brain.
    27. (1998). Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and in vivo.
    28. (2000). Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord.
    29. (2001). Proliferation of NG2-positive cells and altered oligodendrocyte numbers in the contused rat spinal cord.
    30. (2007). Prominent oligodendrocyte genesis along the border of spinal contusion lesions.
    31. (2002). Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor.
    32. (2007). Temporal-spatial dynamics in oligodendrocyte and glial progenitor cell numbers throughout ventrolateral white matter following contusion spinal cord injury.
    33. (2003). The biology of VEGF and its receptors.
    34. (2005). Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.
    35. (1991). Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator.
    36. (2000). Vascular endothelial cell growth factors promote the in vitro development of rat photoreceptor cells.
    37. (2002). Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo.
    38. (1999). Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system.
    39. (2003). Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury.
    40. (2004). Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures.
    41. (2001). Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades.
    42. (2000). Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia.
    43. (2003). VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.