Bone fat squelches new blood

Fat cells have long been considered to be mere filler in bone marrow, but linkurl:a study published online today;http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08099.html in Nature reports that these cells serve an important function -- namely, they put the brakes on blood formation. Grey's Anatomy illustrationof human bone marrow Image: Wikipedia "I think it's fundamentally important," linkurl:Sean Morrison,;http://www.med.umich.edu/cdb/sub_pages/people/morrison.htm director of

Written byAlla Katsnelson

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Grey's Anatomy illustration
of human bone marrow
Image: Wikipedia

"I think it's fundamentally important," linkurl:Sean Morrison,;http://www.med.umich.edu/cdb/sub_pages/people/morrison.htm director of the University of Michigan's Center for Stem Cell Biology, who was not involved in the research, said of the finding. "Adipocytes have not been among the cells that have been hypothesized to regulate hematopoietic stem cell function." "The classic teaching in medical school," explained main author linkurl:George Daley;http://daley.med.harvard.edu/ of the Harvard Stem Cell Institute and Children's Hospital Boston, is that adipocytes act as a kind of passive padding in the bone marrow. Instead, researchers have largely focused on bone marrow osteoblasts and, to a lesser extent, endothelial cells, as regulators of hematopoietic stem cell function. Fat, however, has a large presence in the bone marrow, taking up an increasing proportion of space there with age. "We wanted to ask whether [fat] is actually physiologically involved," Daley said. Daley and his colleagues first characterized the levels of adipocytes in normal mouse bone marrow. When the marrow is rich in adipocytes, they found, it contains fewer blood progenitor cells, and those that are present divide less frequently. They then analyzed hematopoiesis in so-called "fatless" mice, which have a genetic defect that prevents them from forming adipocytes. When they destroyed their bone marrow using irradiation and replaced it with marrow from normal animals, the transplanted hematopoietic progenitors regenerated significantly more rapidly than in similar experiments in wild-type animals. In a third series of studies, the researchers found that pharmacologically blocking fat formation after bone marrow transplantation in normal mice also improves the rate at which blood progenitors regrow. "I think we're learning that the marrow space, like lots of tissue, is an elaborate choreography among several players," said Daley. Indeed, he added, it appears as though these players are regulating not just hematopoiesis, but also each other. When the group irradiated the fatless mice, for example, "we saw not only increased blood formation, but also a very dramatic bony response," said Daley. "So the bone is probably also regulated by fat." The fatless mice experiments conclusively nail down the role of adipocytes as negative regulators of hematopoiesis, said Morrison. "In no case have experiments [on other potential regulators] so definitively [shown] a regulatory role" as in this paper, he said. "There's good evidence that osteoblasts are doing something, but it's not quite clear exactly what." Daley said his group is now trying to pin down how exactly fat cells perform their regulatory role, and taking a closer look at adipocyte-targeting compounds under development as obesity treatments. "We're testing them now on bone marrow," he said, with the hope that these compounds could one day spur blood formation in patients who have undergone bone marrow transplants. Meanwhile, said Morrison, the study raises further questions about how blood formation is regulated. "George [Daley] is showing that fat cells negatively regulate hematopoietic stem cells," he said, "which leaves the question of which cells positively regulate hematopoietic stem cells wide open." Osteoblasts are good candidates, he added, "but there's a lot more work to be done to figure out the mechanism."

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