Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment

Abstract

Adult bone marrow contains numerous adipocytes, whose numbers correlate inversely with the haematopoietic activity. Disorders of excess haematopoiesis, such as pernicious anaemia and leukaemia, are typically accompanied by haematopoietic infiltration of the fatty marrow of the long bones. It has been unclear whether adipocytes participate in haematopoietic regulation or simply expand to fill marrow space. The answer appears to be that far from making up the numbers, fat cells play a critical physiological role in the bone marrow microenvironment. Experiments in mice show that adipocyte-rich marrow contains fewer blood-forming stem cells and progenitors than adipocyte-poor marrow. Genetically 'fat-free' mice and mice treated with a drug that blocks adipocyte production generated new blood cells more quickly than wild-type animals after a bone-marrow transplant, suggesting that blocking marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation. Adult bone marrow contains numerous adipocytes, the numbers of which correlate inversely with the haematopoietic activity of the marrow. It had been unclear whether adipocytes participate in haematopoietic regulation or simply expand to fill marrow space; here it is shown that murine haematopoiesis is reduced in adipocyte-rich marrow during homeostasis, and that adipocytes antagonize haematopoietic recovery after bone-marrow irradiation. Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow1,2,3. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia4. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 ‘fatless’ mice, which are genetically incapable of forming adipocytes5, and in mice treated with the peroxisome proliferator-activated receptor-γ inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis6, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.