Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    Article  CAS  ADS  Google Scholar 

  2. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    Article  CAS  ADS  Google Scholar 

  3. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. & Morrison, S. J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005)

    Article  CAS  Google Scholar 

  4. Bryon, P. A., Gentilhomme, O. & Fiere, D. Histomorphometric analysis of bone-marrow adipose density and heterogeneity in myeloid aplasia and dysplasia. Pathol. Biol. 27, 209–213 (1979)

    CAS  PubMed  Google Scholar 

  5. Moitra, J. et al. Life without white fat: a transgenic mouse. Genes Dev. 12, 3168–3181 (1998)

    Article  CAS  Google Scholar 

  6. Wright, H. M. et al. A synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiation. J. Biol. Chem. 275, 1873–1877 (2000)

    Article  CAS  Google Scholar 

  7. Neumann E Das Gesetz Verbreitung des gelben und rotten Markes in den Extremitätenknochen. Zentbl. Med. Wiss. 18, 321–323 (1882)

    Google Scholar 

  8. Calvo, W., Fliedner, T. M., Herbst, E., Hügl, E. & Bruch, C. Regeneration of blood-forming organs after autologous leukocyte transfusion in lethally irradiated dogs. II. Distribution and cellularity of the marrow in irradiated and transfused animals. Blood 47, 593–601 (1976)

    CAS  PubMed  Google Scholar 

  9. Litten, M. & Orth, J. Ueber Veränderungen des Marks in Röhrenknochen unter verschiedenen pathologischen Verhältnissen. Berl. Klin. Wschr. 51, 743–751 (1877)

    Google Scholar 

  10. Christensen, J. L. & Weissman, I. L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl Acad. Sci. USA 98, 14541–14546 (2001)

    Article  CAS  ADS  Google Scholar 

  11. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996)

    Article  CAS  ADS  Google Scholar 

  12. Pan, Z. et al. Effects of hindlimb unloading on ex vivo growth and osteogenic/adipogenic potentials of bone marrow-derived mesenchymal stem cells in rats. Stem Cells Dev. 17, 795–804 (2008)

    Article  CAS  Google Scholar 

  13. Yang, L. et al. Identification of Lin-Sca1+kit+CD34+Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood 105, 2717–2723 (2005)

    Article  CAS  Google Scholar 

  14. Tavassoli, M., Maniatis, A. & Crosby, W. H. Induction of sustained hemopoiesis in fatty marrow. Blood 43, 33–38 (1974)

    CAS  PubMed  Google Scholar 

  15. Botolin, S. & McCabe, L. R. Inhibition of PPARγ prevents type I diabetic bone marrow adiposity but not bone loss. J. Cell. Physiol. 209, 967–976 (2006)

    Article  CAS  Google Scholar 

  16. Furuhashi, M. et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959–965 (2007)

    Article  CAS  ADS  Google Scholar 

  17. Digman, C., Klein, A. K. & Pittas, A. G. Leukopenia and thrombocytopenia caused by thiazolidinediones. Ann. Intern. Med. 143, 465–466 (2005)

    Article  Google Scholar 

  18. Maaravi, Y. & Stessman, J. Mild, reversible pancytopenia induced by rosiglitazone. Diabetes Care 28, 1536 (2005)

    Article  Google Scholar 

  19. Berria, R. et al. Reduction in hematocrit and hemoglobin following pioglitazone treatment is not hemodilutional in Type II diabetes mellitus. Clin. Pharmacol. Ther. 82, 275–281 (2007)

    Article  CAS  Google Scholar 

  20. Lazarenko, O. P. et al. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148, 2669–2680 (2007)

    Article  CAS  Google Scholar 

  21. Nishikawa, M. et al. Changes in hematopoiesis-supporting ability of C3H10T1/2 mouse embryo fibroblasts during differentiation. Blood 81, 1184–1192 (1993)

    CAS  PubMed  Google Scholar 

  22. Corre, J. et al. Human subcutaneous adipose cells support complete differentiation but not self-renewal of hematopoietic progenitors. J. Cell. Physiol. 208, 282–288 (2006)

    Article  CAS  Google Scholar 

  23. Belaid-Choucair, Z. et al. Human bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition. Stem Cells 26, 1556–1564 (2008)

    Article  CAS  Google Scholar 

  24. Miharada, K. et al. Lipocalin 2-mediated growth suppression is evident in human erythroid and monocyte/macrophage lineage cells. J. Cell. Physiol. 215, 526–537 (2008)

    Article  CAS  Google Scholar 

  25. Yan, Q. W. et al. The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance. Diabetes 56, 2533–2540 (2007)

    Article  CAS  Google Scholar 

  26. Yokota, T. et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96, 1723–1732 (2000)

    CAS  PubMed  Google Scholar 

  27. Zhang, Y. et al. Tumor necrosis factor (TNF) is a physiologic regulator of hematopoietic progenitor cells: increase of early hematopoietic progenitor cells in TNF receptor p55-deficient mice in vivo and potent inhibition of progenitor cell proliferation by TNFα in vitro. Blood 86, 2930–2937 (1995)

    CAS  PubMed  Google Scholar 

  28. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993)

    Article  CAS  ADS  Google Scholar 

  29. DiMascio, L. et al. Identification of adiponectin as a novel hemopoietic stem cell growth factor. J. Immunol. 178, 3511–3520 (2007)

    Article  CAS  Google Scholar 

  30. Nuttall, M. E. & Gimble, J. M. Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications. Curr. Opin. Pharmacol. 4, 290–294 (2004)

    Article  CAS  Google Scholar 

  31. Pozarowski, P. & Darzynkiewicz, Z. Analysis of cell cycle by flow cytometry. Methods Mol. Biol. 281, 301–311 (2004)

    CAS  PubMed  Google Scholar 

  32. Goodell, M. A., Brose, K., Paradis, G., Conner, A. S. & Mulligan, R. C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183, 1797–1806 (1996)

    Article  CAS  Google Scholar 

  33. Wilson, A. et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 18, 2747–2763 (2004)

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to George Q. Daley.

Ethics declarations

Competing interests

The subject matter of the publication is the basis for a patent application.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-10 with Legends. (PDF 1126 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08099

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing