Stem cells get a cholesterol test

I n addition to responding to changes in their local microenvironment, stem cells are regulated by systemic changes, such as the availability of nutrients in an organism's diet. In Drosophila, for example, egg production—which relies on the proliferation of both germline stem cells (GSCs) and follicle stem cells (FSCs)—is switched off when food is scarce and reactivated when conditions improve (1). Hartman et al. reveal that dietary cholesterol levels regulate FSC proliferation by controlling the release of Hedgehog (Hh) protein (2). GSCs, which give rise to the nurse cells and oocyte of Drosophila ovaries, are regulated by insulin signaling. On the other hand, FSCs, which proliferate to form an outer layer of epithelial follicle cells, are stimulated by Hh and other proteins released from nearby cells in the ovary called apical cells. Alana O'Reilly, Tiffi ney Hartman, and colleagues at the Fox Chase Cancer Center in Philadelphia have previously shown that the Hh receptor Boi limits Hh release and FSC proliferation by sequestering Hh on the surface of apical cells (3). " We were interested in identifying the pathway that triggers Hh's release from Boi, " O'Reilly says. " And we thought that changes in nutrient levels might alter the equilibrium between sequestra-tion and release to control stem cell proliferation. " When Hartman et al. placed female fl ies on a restricted diet of water and a few simple sugars, Hh remained on the surface of apical cells, and FSC proliferation and egg production were shut down (2). Refeeding the fl ies with nutrient-rich yeast, however, quickly prompted Hh's release from apical cells and its accumulation in proliferating FSCs. " We started fractionating yeast to fi nd out what the critical nutrient was, [and we discovered that] it had to be a lipid, " O'Reilly explains. " There's only one lipid required in the diet of fl ies, and that's cholesterol. " Sure enough, feeding nutrient-restricted flies with lipid-free yeast extract plus cholesterol stimulated Hh release and FSC proliferation. " One of the main roles of follicle cells is to produce yolk, " O'Reilly says. " So cholesterol may be the trigger because these cells depend on it to generate yolk and produce a viable egg. " " As soon as we knew that cholesterol was the key nutrient, " O'Reilly continues, " we looked at its receptor, DHR96. " Starving fl ies whose apical cells lacked DHR96 failed to …