Hormonal signaling in the fruit fly ovary keeps the niche young
Insulin reverses the effects of aging and poor diet, at least on cells within the ovaries of fruit flies. Biologists Daniela Drummond-Barbosa and Hwei-Jan Hsu of Vanderbilt University in Nashville, Tennessee, found that boosting levels of insulin-like peptides slowed down the decline in stem cell numbers and function that normally occurs as flies age. The hormone does not act on the stem cells directly, but rather via the niche — the cells that form a stem cell's support system.
Hormones probably influence most niches, though surprisingly little is known about it, says Erika Matunis of John Hopkins University in Baltimore, Maryland, who studies how stem cells maintain sperm production in fruit flies and was not involved in the study. "At this point the fly ovary is yielding by far the most detailed glimpse into the interactions of hormonal signaling and stem cell niches."
"Normally, a lot of research on niches is concentrated on local factors produced by the niche that affect stem cells," says Drummond-Barbosa. "In this paper, we take a broader view to understand how these local microenvironments can be impacted by the environment where the organism lives."
Though germline stem cells decline in number over time even in flies fed a healthy diet of yeast and molasses, the decline is much swifter if flies are fed a nutrient-poor diet of molasses alone. This observation is partly explained by the fact that diet affects insulin signaling. The loss of germline stem cells over time was stalled if flies were engineered to express a Drosophila peptide similar to insulin.
However, when the researchers made flies that were 'genetic mosaics', meaning each fly had cells with one of two mutant versions of the insulin receptor protein, they discovered that stem cells with either version behaved similarly. (Both types were equally likely to remain stem cells or differentiate.) Next, the researchers engineered the flies so that only cells in the niche expressed the receptor. "That was able to restore normal stem cell numbers," says Drummond-Barbosa. "The insulin signals are acting on the niche." Further work showed that the signals have at least two effects: one allows the stem cells to adhere to the other cells within the niche, whereas a second increases the levels of a protein called Notch, already known to help maintain niche cells.The study did not explore how the effects of insulin on germline stem cells extend flies' lifespan or improve their overall health, cautions Drummond-Barbosa. Much data indicates that insulin accelerates aging; it is possible, for instance, that the loss of germline stem cells improves longevity.
The paper "uncovers key age-related changes" that cause stem cell loss in aging flies and "greatly improves our understanding of the biochemical pathways regulating stem cell–niche interactions," says Irina Conboy of University of California, Berkeley, who studies how pathways that maintain muscle stem cells change as mice age. "It would be certainly very interesting to examine the evolutionary conservation of these age-responsive biochemical interactions."
Drummond-Barbosa is now looking for more body-wide signals besides insulin that affect stem cells. "If we take old flies that are overexpressing insulin in the niche, the rescue is not complete," she says. "It's important to get beyond the niche" and explore the role of diet, environment and system-wide factors. Manipulating stem cells "from outside the organism," she believes, could make for easier, less-invasive therapies.
- Hsu, H-J. & Drummond-Barbosa, D. Insulin levels control female germline stem cell maintenance via the niche in Drosophila. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0809144106 (published online 9 January 2009). | Article |
- Monya Baker is editor of Nature Reports Stem Cells