Adult neural stem cell self-regulation via soluble growth factor

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Brain stem cells have great potential for treating neurological disorders, but this potential remains unrealized because of an incomplete understanding of how these cells maintain their immature status. In the brain of adult mammals, neural stem cells are found in a few, isolated places, including the hippocampus, where they continue to create new neurons that contribute to healthy memory function. Pilot data generated for this proposal found that adult hippocampal neural stem cells express a biochemical growth factor (vascular endothelial growth factor [VEGF]) that is essential for their long-term survival and maintenance. VEGF may act on these cells in several possible ways, and the proposed studies will determine which of these possible mechanisms VEGF uses to maintain brain stem cells. The results of this research will have a major impact on the design of stem cell-based therapies by revealing mechanisms that growth factors use to support stem cells and enhance their survival. In addition, this work will have an impact on the local community via a specialized program promoting high school stem cell education, support for a new Brain Bee outreach program, and general outreach that will educate the public about stem cell biology and its potential role in medicine. The persistence of neural stem cells (NSCs) in the adult mammalian hippocampus is highly conserved across species, yet the molecular mechanisms that regulate maintenance of these NSCs are unresolved. Numerous studies show that local signals from neighboring cells help maintain NSCs, but less attention has been given to how NSCs self-regulate. Our preliminary data show that adult hippocampal NSCs and their progenitor progeny (NSPCs) self-maintain their own stemness via expression of vascular endothelial growth factor (VEGF). While soluble proteins are classically conceptualized as signaling by binding to receptors on the cell surface, they can also act through two alternative routes that are less-frequently studied: 1) via intracrine activation of receptors in endocytic vesicles, and 2) via transmission between cells in exosomes. Pilot data show that VEGF exists in all of these cellular compartments, but which ones are essential for VEGF maintenance of stemness is unknown. The proposed experiments will use in-vitro and in-vivo murine models to determine which of these methods of VEGF transmission (paracrine extracellular, intracrine and/or paracrine exosomal) are active in NSPCs and essential for self-maintenance of stemness. The proposed work will provide a major advance in understanding for the largely uninvestigated field of non-canonical pathways for adult NSPC self-maintenance via soluble signals.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.