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A neural stem/progenitor cell based approach for brain repair

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Defense Thèse de doctorat : Univ. Genève, 2010 - Sc. 4238 - 2010/07/16
Abstract The postnatal mammalian cortex has a very limited capacity for neuronal replacement after brain injury. One of the reasons for this restricted repair might be the lack of available neural progenitors. A promising approach is to transplant new cells in the rat cerebral cortex aiming at reconstructing the damaged brain. However the efficiency of these approaches for neuronal replacement in vivo remains very limited. After transplantation of NPCs into the cortex, the number of cells that survive and differentiate into new neurons is exceedingly low. Among the multiple factors limiting the efficiency of NPCs after transplantation in the postnatal cortex is the fact that grafted NPCs rapidly lose their immature, proliferative and migratory properties. A major challenge is to develop pre-transplant cell manipulations that may promote the survival, engraftment and differentiation of transplanted cells. For this purpose, we investigated the possibility that over-expression of fibroblast growth factor-2 (FGF-2), a strong niche factor, in NPCs could improve their potential for structural brain repair. In the first part of the thesis we showed that lentiviral overexpression of FGF-2 in NPCs provides a source of multipotential, proliferative and migrating NPCs that can efficiently invade the injured cortex and generate an increased pool of immature neurons available for brain repair. In the second part of the thesis, we demonstrated that FGF-2 overexpressing NPCs associate preferentially with host blood vessels, generating neurovascular clusters. The close interaction between transplanted NPCs and the host vasculature appeared to be critical in maintaining NPCs in an undifferentiated and proliferative state. Furthermore, these neurovascular ectopic "clusters" seemed to preserve the potential to generate new neurons after being challenged by an ischemic insult. Together, these datas reveal an essential role for FGF-2 in regulating NPCs functions when interacting with the host tissue, essentially by generating "ectopic" neurovascular clusters and offer a novel strategy to generate a robust source of migrating and immature progenitors for repairing an ischemic cortex.
Keywords Neural progenitor cellsFGF-2Brain repairCerebral ischemiaTransplantationNeurovascular clustersMigration
Stable URL https://archive-ouverte.unige.ch/unige:14942
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URN: urn:nbn:ch:unige-149421
Structures
Research group Progéniteurs neuronaux (141)

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Deposited on : 2011-04-11

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