Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF

The adult hippocampus hosts a population of neural stem and progenitor cells (NSPCs) that proliferates throughout the mammalian life span. To date, the new neurons derived from NSPCs have been the primary measure of their functional relevance. However, recent studies show that undifferentiated cells may shape their environment through secreted growth factors. Whether endogenous adult NSPCs secrete functionally relevant growth factors remains unclear. We show that adult hippocampal NSPCs secrete surprisingly large quantities of the essential growth factor VEGF in vitro and in vivo. This self-derived VEGF is functionally relevant for maintaining the neurogenic niche as inducible, NSPC-specific loss of VEGF results in impaired stem cell maintenance despite the presence of VEGF produced from other niche cell types. These findings reveal adult hippocampal NSPCs as an unanticipated source of an essential growth factor and imply an exciting functional role for adult brain NSPCs as secretory cells.In the adult brain, two major neurogenic niches persist throughout the mammalian life span: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus. Resident neural stem and progenitor cells (NSPCs) in each of these areas proliferate and give rise to new neurons that migrate and integrate into existing circuitry in the olfactory bulb or dentate gyrus (DG), respectively. Particularly in the DG, where neurogenesis is found in both rodents and humans, newly born neurons play critical roles in facilitating memory function (1, 2). This role of new neurons in memory is currently considered the dominant functional output of adult neurogenesis. However, recent research has revealed that transplanted embryonic stem cells can aid in injury recovery by secreting growth factors while undifferentiated (3, 4). The secretion of functionally relevant growth factors from endogenous adult hippocampal NSPCs has yet to be reported.We recently showed that cultured neonatal hippocampal progenitors secrete surprisingly large quantities of VEGF compared with astrocytes, microglia, and neurons (5), raising the possibility that NSPCs could be an unexpected source of this essential growth factor in the brain. Within the adult brain, VEGF (also known as VEGF-A) is a potent angiogenic and neurogenic growth factor (6–13). Although several studies have previously noted VEGF expression in cultured adult NSPCs (14, 15), the relative quantity and function of this VEGF are not clear, particularly in vivo, where other cellular sources of VEGF abound. We therefore investigated the contribution of NSPCs to hippocampal VEGF production and the functional role of NSPC-derived VEGF in maintaining the neurogenic niche.