Adult neural stem cells reside in a specialized niche that supports their self-renewal and maintains their ability to generate neurons. When removed from the niche and transplanted into non-neurogenic sites, stem cells make few, if any, neurons. Understanding the interaction between stem cells and their microenvironment in adult neurogenic zones such as the forebrain sub-ventricular zone (SVZ) is an important step towards the long-term goal of designing novel therapeutic strategies for CMS repair. We recently discovered that stem cells reside close to blood vessels in the SVZ, and that endothelial cells dramatically stimulate neural stem cell self-renewal and neuron-production. This suggests endothelial cells are a key component of the neural stem cell niche, and could be a target for manipulating endogenous or transplanted stem cells.
We aim to understand the in vivo relationship between endothelial cells and neural stem cells in the adult mouse SVZ. Detailed spatial characterization in brain sections and whole mount SVZ tissue will be carried out using immunohistochemistry, 2D and 3D image analysis with quantification. We will investigate whether stem cells in the SVZ home to endothelial cells by transplanting marked stem cells into the normal SVZ. The disposition and fate of embryonic or adult enriched neural stem cells transplanted into the niche will be examined. This will allow us to address the important question of whether cortical stem cells continue to make pyramidal projection neurons in this adult neurogenic niche. We will examine expression and function of vascular adhesion molecule (VCAM-1), which is up-regulated in neural stem cells exposed to endothelial factors, and which plays a critical role in blood stem cell homing, adhesion and self-renewal but which has not yet been examined in the neural system. This will be done in vitro and in vivo using lentiviral siRNA knockdown and overexpression. Finally, we will carry out a comparative proteomics study to identify factors released by endothelial cells, candidates for self-renewal and neurogenic factors.
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