Pigment epithelium–derived factor is a niche signal for neural stem cell renewal

Abstract

Adult stem cells are characterized by self-renewal and multilineage differentiation, and these properties seem to be regulated by signals from adjacent differentiated cell types and by extracellular matrix molecules, which collectively define the stem cell "niche." Self-renewal is essential for the lifelong persistence of stem cells, but its regulation is poorly understood. In the mammalian brain, neurogenesis persists in two germinal areas, the subventricular zone (SVZ) and the hippocampus, where continuous postnatal neuronal production seems to be supported by neural stem cells (NSCs). Here we show that pigment epithelium-derived factor (PEDF) is secreted by components of the murine SVZ and promotes self-renewal of adult NSCs in vitro. In addition, intraventricular PEDF infusion activated slowly dividing stem cells, whereas a blockade of endogenous PEDF decreased their cycling. These data demonstrate that PEDF is a niche-derived regulator of adult NSCs and provide evidence for a role for PEDF protein in NSC maintenance.

A Comparative Proteomic Analysis of Human and Rat Embryonic Cerebrospinal Fluid

“…PEDF has also been shown to be secreted by adult murine subventricular zone cells and maintains a niche for adult neuronal stem cells. 35 It is likely that PEDF is released by the photoreceptor cells or proliferating neuronal progenitor cells into the matrix and taken up by the CSF and may act on cell types and neurons by diffusion through the CSF. Similarly, the Neuronal Cell Adhesion Molecule L1-Like Protein, also found only in the human e-CSF, is known to play important roles in neurite outgrowth and neuronal survival.…”

The cancer stem cell hypothesis: in search of definitions, markers, and relevance

“…For example, endothelial cells were shown to be critical for maintenance of neural stem cells and it appears that CD133 þ brain tumor stem cells may also require such niche. [15][16][17] Based on these data demonstrating the necessity of the niche for maintenance of both normal and cancer stem cells, the question is, how is it possible that in 'sphere cultures' cells alone without any ECM attachment display a stem cell phenotype? Previous studies have also described that cells in suspension upregulate many pro-survival pathways, increase their antioxidant levels, and as a consequence become resistant to apoptosis.…”

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…In the SGZ of the adult CNS, mitotic cells are closely associated with blood vessels (Palmer et al, 2000). Endothelial cells in coculture with neural stem cells were found to release soluble factors that increase self-renewal of the stem cells, an effect that is likely to be mediated through VEGF-C/VEGFR-3 and/or pigment epithelium derived factor (PEDF) (Shen et al, 2004;Le Bras et al, 2006;Ramirez-Castillejo et al, 2006) Additionally, basal-lamina-like extensions (called fractones) extend from blood vessels in the SEZ and make contact with all cells in the niche providing a source of ECM containing collagen-IV, laminins, perlecan, nidogen and, in some cases, heparan sulfate proteoglycans (HSPG). These likely send important signals to the stem cells that may include the presentation of FGF-2, which binds to fractone HSPG (Mercier et al, 2002;Kerever et al, 2007).…”