Age-related changes in neural stem cell properties and cellular composition in neurogenic niches of the adult rat brain.

摘要

Neurogenesis persists in two distinct regions of the adult mammalian brain, the subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of hippocampal dentate gyrus. In the SVZ, neural stem/precursor cells proliferate, aggregate into long chains and migrate rostrally toward the olfactory bulb via the rostral migratory stream (RMS). The migratory neuroblasts proliferate as they traverse the RMS and give rise to granule and periglomerular neurons of the olfactory bulb throughout life. We investigated age-related changes in the neurogenic microenvironment and the neural stem/progenitor cell properties in the aging SVZ/RMS. Results revealed a decline in neural stem/progenitor cell proliferation in the SVZ/RMS of mid-aged (12 month old) and aged (22-24 month old) rats compared to young (2 month old) animals. To understand the possible mechanisms for age-related decline in proliferation, we investigated changes in cell cycle kinetics in the aging RMS and found no changes in cell cycle length. We used Sox-2, a putative neural stem/progenitor cell marker, to evaluate age-related changes in the neural stem cell pool in the aging RMS. Our results showed age-related decline in the total number of Sox-2-immunolabeled cells, indicating that the reduced pool of neural/stem progenitor cell may contribute to the age-related reduction in proliferation. Neurogenic microenvironment undergoes age-related alterations. FGFR-2, a receptor for FGF-2, shows robust expression in neurogenic regions, but is significantly attenuated in the aged brain, indicating that decline in FGF-2 signaling may contribute to age-related reduction in neurogenesis. To further explore the environmental changes in the neuroenic niches, we evaluated blood vessel density in the aging SVZ/RMS. We found significant positive correlation between the blood vessel density and neural stem/progenitor cell proliferation in the SVZ of the young, mid-aged and aged brains, suggesting that blood vessels contribute to the neurogenic microenvironment and continue to play an important role throughout the aging process. Ablation of the frequently cycling cell population in the RMS with the anti-mitotic drug, Ara-C, revealed the presence of the endogenous slowly cycling neural stem cell population in this germinal region of the young and aged brains. This finding suggests that the RMS is a discrete neurogenic region, which harbors slowly cycling neural stem cells, rather than being simply an inert conduit for migratory neuroblasts. Our results also indicate that this region of the aged brain retains the neural stem cell population, which could potentially be stimulated for the therapeutic brain repair and regeneration.