Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment

Abstract

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.

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Figure 1: Haematopoietic stem cells and progenitors are reduced in number, frequency and cycling capacity in adipocyte-rich bone marrow during homeostasis.
Figure 2: Lack of bone-marrow adipocytes after irradiation in fatless mice enhances haematopoietic progenitor expansion and post-transplant recovery.
Figure 3: Ablation of the haematopoietic compartment in fatless A-ZIP/F1 mice during bone-marrow transplantation induces osteogenesis.
Figure 4: Pharmacological inhibition of adipocyte formation enhances bone-marrow engraftment in wild-type mice.

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Acknowledgements

We thank S. Lazo-Kallanian, J. Daley, G. Losyev and R. Mathieu for assistance with flow cytometry; R. Bronson for assistance with pathological analysis; P. Dunning, E. Snay and S. Carlton for assistance with small animal imaging; S. Loewer for translation of historical references; and S. McKinney-Freeman, A. Yabuuchi, K. Ng and R. Chapman for mouse and technical assistance. O.N. was partially funded by the Barrie de la Maza Foundation. P.L.W. was supported by a Hematology Training Grant from the National Institutes of Health (NIH T32- HL -7623). G.Q.D. was supported by grants from the NIH and the NIH Director’s Pioneer Award of the NIH Roadmap for Medical Research. G.Q.D. is the recipient of the Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and is an Investigator of the Howard Hughes Medical Institute.

Author Contributions O.N and G.Q.D. conceived the original idea, designed experiments and wrote the manuscript. O.N., V.N. and P.L.W. performed experiments and analysed results. P.V.H. contributed to stromal differentiation essays. O.N. and F.F. performed quantitative acquisition and analysis of mCT and mPET. All authors edited and reviewed the final manuscript.

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Correspondence to George Q. Daley.

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Naveiras, O., Nardi, V., Wenzel, P. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009) doi:10.1038/nature08099

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