Transplantation of embryonic neural stem/precursor cells overexpressing BM88/Cend1 enhances the generation of neuronal cells in the injured mouse cortex

Stem Cells. 2010 Jan;28(1):127-39. doi: 10.1002/stem.258.

Abstract

The intrinsic inability of the central nervous system to efficiently repair traumatic injuries renders transplantation of neural stem/precursor cells (NPCs) a promising approach towards repair of brain lesions. In this study, NPCs derived from embryonic day 14.5 mouse cortex were genetically modified via transduction with a lentiviral vector to overexpress the neuronal lineage-specific regulator BM88/Cend1 that coordinates cell cycle exit and differentiation of neuronal precursors. BM88/Cend1-overexpressing NPCs exhibiting enhanced differentiation into neurons in vitro were transplanted in a mouse model of acute cortical injury and analyzed in comparison with control NPCs. Immunohistochemical analysis revealed that a smaller proportion of BM88/Cend1-overexpressing NPCs, as compared with control NPCs, expressed the neural stem cell marker nestin 1 day after transplantation, while the percentage of nestin-positive cells was significantly reduced thereafter in both types of cells, being almost extinct 1 week post-grafting. Both types of cells did not proliferate up to 4 weeks in vivo, thus minimizing the risk of tumorigenesis. In comparison with control NPCs, Cend1-overexpressing NPCs generated more neurons and less glial cells 1 month after transplantation in the lesioned cortex whereas the majority of graft-derived neurons were identified as GABAergic interneurons. Furthermore, transplantation of Cend1-overexpressing NPCs resulted in a marked reduction of astrogliosis around the lesioned area as compared to grafts of control NPCs. Our results suggest that transplantation of Cend1-overexpressing NPCs exerts beneficial effects on tissue regeneration by enhancing the number of generated neurons and restricting the formation of astroglial scar, in a mouse model of cortical brain injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries / genetics
  • Brain Injuries / metabolism
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology
  • Brain Injuries / therapy*
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / transplantation*
  • Female
  • Genetic Therapy*
  • Genetic Vectors
  • Green Fluorescent Proteins / genetics
  • Immunohistochemistry
  • Intermediate Filament Proteins / metabolism
  • Lentivirus / genetics
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Cortex / embryology
  • Motor Cortex / injuries
  • Motor Cortex / metabolism
  • Motor Cortex / pathology
  • Motor Cortex / physiopathology*
  • Motor Skills
  • Nerve Regeneration*
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / transplantation*
  • Recovery of Function
  • Spheroids, Cellular
  • Stem Cell Transplantation*
  • Swine
  • Time Factors
  • Transduction, Genetic

Substances

  • Cend1 protein, mouse
  • Intermediate Filament Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Green Fluorescent Proteins