The therapeutic recruitment of endogenous neural stem/progenitor cells provides a glimmer of hope for reversing the devastating loss of function that accompanies central nervous system injury. To better understand neural stem cell behavior in vivo, we have completed a detailed anatomical study of adult hippocampal neurogenesis. An unexpected finding is that angiogenesis accompanies neurogenesis and may be an essential requisite for the de novo generation of neurons from adult neural stem cells. To determine the importance of angiogenesis in adult neurogenesis, it will be necessary to block and stimulate angiogenesis in vivo, preferably without simultaneously perturbing stem cell mitogenesis. Preliminary data shows that FGF-2, EGF, and VEGF are mitogens for both endothelium and neural stem cells. This warns against the use of the readily available antagonists that target VEGF or FGF-2 receptors (or the more generic MAP kinase pathway inhibitors) since these may not be useful for our attempts to uncouple angiogenesis from neurogenesis. Fortunately, we have found that a synthetic mimetic of vitronectin is able to block integrin avb3 signaling and inhibits endothelial cell but not neural stem cell proliferation in culture. These studies will provide important insights into the microenvironments that control """"""""adult"""""""" neural stem cell activity and fate. The primary methodologies will be IV administration of synthetic integrin antagonists to block angiogenesis. These data will be contrasted to local stimulation of angiogenesis by VEGF gene transfer. Neurogenesis in experimental animals will be monitored with systemic BrdU-labeling, post-hoc stereology and confocal analysis.
| Wexler, Eric M; Paucer, Andres; Kornblum, Harley I et al. (2009) Endogenous Wnt signaling maintains neural progenitor cell potency. Stem Cells 27:1130-41 |
| Fabel, Klaus; Fabel, Konstanze; Tam, Betty et al. (2003) VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18:2803-12 |
