Researchers have long known that fat will move into the placesleft behind when blood-producing cells are destroyed by chemotherapy or irradiation. New work, however, suggests that there is more going on. “We were taught in med school that fat was a space filler in the marrow, inversely proportional to haematopoietic content,” says George Daley of Children’s Hospital Boston. “What we show is that the fat actively influences HSC [haematopoietic stem cell] activity.” More specifically, Daley’s team shows that discouraging fat production in the marrow actually helps HSCs engraft1. This has important implications for helping patients recover after bone marrow transplants.
Previous work on the bone-marrow niche had focused on the bone-forming osteoblasts and the pericytes found around capillaries, says Sean Morrison of the University of Michigan in Ann Arbor, who was not part of the study. “This paper presents some of the most convincing data we have so far implicating a specific cell type as a physiological regulator of stem cell function and haematopoiesis.”
The researchers began their work by comparing the relative amounts of fat- and bone-producing cells in different mouse vertebrae. Compared with vertebrae in the upper back, tail vertebrae had the highest percent of fat and also had 25% as many haematopoietic cells, as measured by the marker CD45. Next, they simulated the effects of radiation therapy and bone marrow transplantation in normal mice and genetically engineered fatless mice. Weeks after transplant, the fatless mice had more haemoglobin and white blood cells in their blood. Finally, they tested whether a compound known to keep fat from forming in the bone marrow could increase both haematopoiesis and bone marrow engraftment. More specifically, the treatment used a compound called BADGE (bisphenol A diglycidyl ether) that inhibits peroxisome proliferator–activated receptor-gamma (PPAR-gamma) and stalls adipocyte formation in the bone marrow, at least in mice rendered diabetic through doses of streptozotocin. The results might also reveal why experimental diabetes drugs designed to work by activating PPAR-gamma might reduce blood formation in the marrow.
Daley thinks there is likely an “orchestra” of several cell types interacting in the bone marrow niche to influence haematopoiesis. His lab is currently looking into several mediators released from fat cells that could have such effects. Additionally, PPAR-gamma antagonists are currently being studied to treat obesity, and Daley is testing whether these might also help blood systems recover in patients receiving bone marrow transplants. “I think the clinical implications are quite compelling.”
1. Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature advance online publication, doi:10.1038/nature08099 (10 June 2009).