By Nelson Chao, MD

2009-09-01

Dr. Chao indicated no relevant conflicts of interest.

Naveiras O, Nardi V, Wenzel PL, et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460:259-63.

In our current epidemic of obesity, fat is a dreaded word. By some estimates, Americans spend $40 billion per year on weight-loss programs and diets. Now comes yet more evidence that fat is bad … for hematopoiesis. We have learned a lot about hematopoietic niches. Signals imparted from these cells directly contribute to the fate of the stem cells, whether by direct signaling or gradients of secreted factors and extracellular matrix. The importance of niches for hematopoiesis has been established through alterations of osteoblasts or vascular beds. The conventional wisdom was that as the patient ages or is treated with radiation or chemotherapy, the marrow pulp is gradually replaced by more and more fat (more correctly, by adipocytes), thought to simply “fill in the space.”

The current work by Naveiras et al., from George Daley’s lab, upends this conventional wisdom. They began their studies by comparing the contents of hematopoietic stem cells and their progenitors in different vertebral bodies. In the mouse, the central vertebral bodies (thorax) contain the fewest adipocytes, and as one moves toward the tail, starting at the third or fourth tail segments, it becomes full of adipocytes. The percentage of all hematopoietic progenitor classes was reduced 2- to 3-fold in the adipocyte-rich tail vertebrae compared with the thoracic vertebral bodies. They then tested the effects of radiation and hematopoietic transplantation on a genetically modified mouse, the lipoatrophic “fatless” A-ZIP/F1 mouse, which is unable to form adipocytes. When these fatless mice were compared with normal controls, the fatless mice rescued hematopoiesis in the tail and had higher hemoglobin and white blood cells in the circulation. All the known hematopoietic progenitors were increased in the fatless mouse. Interestingly, however, when comparing short-term versus long-term hematopoietic stem cells in normal animals, the tail vertebral body’s cells resulted in more multilineage, long-term engraftment, suggesting that the residual cells in the tail marrow were more quiescent.

Lastly, they tested whether blocking adipogenesis could have an impact on hematopoiesis. They utilized a compound called biphenol A diglycidyl ether (BADGE) that blocks peroxisome proliferator-activated receptor gamma (PPAR-γ), which was shown to prevent adipocyte formation in the marrow. Animals treated with BADGE after hematopoietic cell transplantation had higher peripheral blood counts and more colony formingunits.

Taken together, these data suggest that, as in most areas of biology, there are positive and negative regulators of most cellular functions. In hematopoiesis, the osteoblasts (and likely other cells) supply a positive signal, whereas the adipocytes appear to be a negative regulator, perhaps keeping the cells in a more quiescent stage. Moreover, the possibility of regulation of adipocytes through inhibiting PPAR-γ or other pathways raises the potential of enhancing engraftment after hematopoietic cell transplantation.

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