Neural stem cells are reported to lie in a vascular niche, but there is no direct evidence for a functional relationship between the stem cells and blood vessel component cells. We show that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulates neuroepithelial cell contact, activating Notch and Hes 1 to promote self-renewal. These findings identify endothelial cells as a critical component of the neural stem cell niche.

There is an emerging understanding of the importance of the vascular system within stem cell niches. Here we examine whether neural stem cells (NSCs) in the adult subventricular zone (SVZ) lie close to blood vessels, using 3-dimensional wholemounts, confocal microscopy and automated computer-based image quantification. We found that the SVZ contains a rich plexus of blood vessels that snake along and within neuroblast chains. Cells expressing stem cell markers, including GFAP, and proliferation markers, are closely apposed to the laminin-containing extracellular matrix (ECM) surrounding vascular endothelial cells. Apical GFAP+ cells are admixed within the ependymal layer and some span between the ventricle and blood vessels, occupying a specialized microenvironment. Adult SVZ progenitor cells express the laminin receptor alpha6beta1 integrin, and blocking this inhibits their adhesion to endothelial cells, altering their position and proliferation in vivo, indicating it plays a functional role in binding SVZ stem cells within the vascular niche.

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Summary Neural progenitor cells (NPCs) in the adult subventricular zone (SVZ) are associated with ependymal and vasculature niches which regulate stem cell self-renewal and differentiation. Activated Type B stem cells and their progeny, the transit amplifying Type C cells, which express EGFR, are most highly associated with vascular cells, indicating that this niche supports lineage progression. Here we show that proliferative SVZ progenitor cells home to endothelial cells in a stromal-derived factor 1 (SDF1) and CXC chemokine receptor 4 (CXCR4) dependent manner. We show that SDF1 strongly upregulates EGFR and α6 integrin in activated type B and type C cells, enhancing their activated state and their ability to bind laminin in the vascular niche. SDF1 increases the motility of Type A neuroblasts, which migrate from the SVZ towards the olfactory bulb. Thus, differential responses to SDF1 can regulate progenitor cell occupancy of and exit from the adult SVZ vascular niche.

The embryonic cerebral cortex contains a population of stem-like founder cells capable of generating large, mixed clones of neurons and glia in vitro. We report that the default state of early cortical stem cells is neuronal, and that stem cells are heterogeneous in the number of neurons that they generate. In low fibroblast growth factor (FGF2) concentrations, most maintain this specification, generating solely neuronal progeny. Oligodendroglial production within these clones is stimulated by a higher, threshold level of FGF2, and astrocyte production requires additional environmental factors. Because most cortical neurons are born before glia in vivo, these data support a model in which the scheduled production of cortical cells involves an intrinsic neuronal program in the early stem cells and exposure to environmental, glia-inducing signals.