Recruitment of endogenous cortical progenitor cells by trophic factor gene delivery.

摘要

This thesis examined naive and recruited endogenous neural progenitor cells in the entorhinal cortex (ECX) of young adult and aged rats. Reports support existence of phenotypically unspecified neural stem cells (NSCs) in gray matter, but they have not been well characterized. Adenoviral gene delivery of fibroblast growth factor 2 (FGF-2) or brain-derived neurotrophic factor (BDNF) to the ECX was used to study effects on local NSCs, as well as downstream hippocampal dentate gyrus NSCs. Newly generated cells were labeled by bromodeoxyuridine (BrdU) followed by determination of their proliferation, differentiation, and survival 1 day, 2 weeks, and 2 months after their birth using confocal stereology.; Results revealed that the vast majority of proliferating cells in the naive ECX express NG2 (oligodendrocyte precursor marker in most conditions) and that the size of the BrdU-labeled cell cohort, which was half in aged compared to young, remains stable over time. Following FGF-2 or BDNF gene delivery, a substantial population of cells was recruited in the ECX, increasing the number of BrdU+ cells approximately 6- or 4-fold, respectively. At 2 months, the population was maintained and even expanded in animals that received BDNF, but not FGF-2, gene delivery. This indicates that FGF-2 increases cortical progenitor cell proliferation, while BDNF increases both proliferation and survival. The recruited population consisted mainly of uncommitted progenitor cells, while those cells that showed lineage commitment coexpressed NG2 or the astrocytic markers S100beta and GFAP. Aged rats showed similar degree of trophic factor responsiveness to that of young, but the size of the recruited cell population was smaller. In young animals receiving BDNF gene delivery, but not FGF-2, a doubling of neurogenesis in dentate gyrus was seen at 2 weeks and 2 months.; These results indicate that trophic factors, in particular BDNF, may be used to recruit cortical and hippocampal NSCs for brain repair and that CNS circuitry may be used for targeted therapeutic delivery. These studies lay the foundation for experiments that will determine whether a combination of trophic factors can be used to specifically direct the expanded progenitor cell population down desired phenotypic lineages.