Transplantation of embryonic neural stem/precursor cells overexpressing BM88/Cend1 enhances the generation of neuronal cells in the injured mouse cortex.
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.
Makri
Georgia
G
Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, 11521 Athens, Greece.
Lavdas
Alexandros A
AA
Katsimpardi
Lida
L
Charneau
Pierre
P
Thomaidou
Dimitra
D
Matsas
Rebecca
R
D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000196:embryology / Q000293:injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009048:Motor Skills; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000637:transplantation*; D020127:Recovery of Function; D018874:Spheroids, Cellular; D033581:Stem Cell Transplantation; D013552:Swine; D013997:Time Factors; D014161:Transduction, Genetic
C496858:Cend1 protein, mouse; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D049452:Green Fluorescent Proteins