Skip to main content
SpringerLink
Log in

Bone Marrow “Yellow” and “Red” Adipocytes”: Good or Bad Cells?

  • Molecular Biology of Bone Marrow Fat Adiposity (B van der Eerden, Section Editor)
  • Published:
Current Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Replacement of red hematopoietic bone marrow with yellow adipocyte-rich marrow constitutes a physiological process associated with aging. Adipocytes have recently emerged as an active part of the bone marrow niche and exert paracrine and endocrine functions, thereby contributing to the regulation of hematopoiesis. Here, we review the current understanding of the interactions between bone marrow adipocytes (BMAs) and hematopoietic cells, as well as their potential role in the progression of hematological malignancies.

Recent Findings

Until recently, BMAs have been considered space-filler cells. Emerging evidence, however, associates BMA abundance with hematopoietic regulation. On the one hand, human clinical data and experimental findings from animal models suggest that BMAs may act as negative regulators of the hematopoietic microenvironment. On the other hand, recent data has also shown BMAs to exert positive effects on hematopoietic stem cell (HSC) survival. These seemingly contradictory effects could be explained either by a differential effect of distinct BMA subtypes on hematopoiesis, or by a differential response to BMA stimulation in HSCs versus their committed progeny. Two distinct types of bone marrow adipocytes have previously been described based on anatomical localization. Adipocytes located in the “yellow” marrow are bigger in size, less responsive to environmental stimuli, and associated with HSC quiescence. On the contrary, adipocytes situated within regions of hematopoietically active “red” marrow are significantly more labile and provide important support to regenerating blood populations. Moreover, beyond the presumed differential role of BMA subtypes in hematopoiesis, an imbalanced proportion of stromal constituents could impair their capacity to provide a protective role. Indeed, if BMA commitment has been shown essential for hematopoietic regeneration, skeletal regions constitutively enriched in BMA would be poorly vascularized, which would in turn negatively affect HSC support. Recently, the interplay of adipocytes and solid cancer has been revealed, with adipocytes promoting the growth of breast, ovarian and prostate cancers. BMAs have been no exception, playing an active role in the support of neoplastic cells in the bone marrow niche, particularly for bone metastatic disease and acute lymphoblastic leukemia (ALL). Acute myeloid leukemia (AML), however, actively suppresses BMAs, which results in impaired myelo-erythroid maturation.

Summary

It is becoming increasingly evident that BMAs are ideally placed to interact with normal and malignant hematopoiesis. As such, elucidating the relationship between BMAs and specific hematopoietic cell types represents a novel avenue to explore therapeutic strategies for the treatment of hematological malignancies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gimble M, Robinson CE, Wu X, Kassem M. The function of adipocytes in the bone marrow stroma: an update. Bone. 1996;19:421–8.

    Article  PubMed  CAS  Google Scholar 

  2. Hardouin P, Pansini V, Cortet B. Bone marrow fat. Joint Bone Spine. 2014;81:313–9.

    Article  PubMed  Google Scholar 

  3. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460:259–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Tuljapurkar SR, McGuire TR, Brusnahan SK, Jackson JD, Garvin KL, Kessinger MA, et al. Changes in human bone marrow fat content associated with changes in haematopoietic stem cell numbers and cytokine levels with aging. J Anat. 2011;219:574–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. •• Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, et al. Adipocyte in the bone marrow during obesity and aging impairs stem cell-based haematopoietic and bone regeneration. Cell Stem Cell. 2017;20(6):771–84. This paper defines a stem cell-like population that gives rise to osteogenic progeny and promotes haematopoietic reconstitution. Aging and high-fat diet reprogram the mesenchymal lineage to preferentially give rise to adipogenic cells that impair haematopoietic and bone regeneration.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. • Mattiucci D, Maurizi G, Izzi V, Cenci L, Ciarlantini M, Mancini S, et al. Bone marrow adipocytes support hematopoietic stem cell survival. J Cell Physiol. 2018;233(2):1500–11. This work demonstrates that bone marrow adipocytes in vitro were able to maintain the survival and the differentiation capability of haematopoietic stem cells after long term culture.

    Article  PubMed  CAS  Google Scholar 

  7. Poloni A, Maurizi G, Serrani F, Mancini S, Zingaretti MC, Frontini A, et al. Molecular and functional characterization of human bone marrow adipocytes. Exp Hematol. 2013;41:558–66.

    Article  PubMed  CAS  Google Scholar 

  8. Corre J, Planat-Benard V, Corberand JX, Pénicaud L, Casteilla L, Laharrague P. Human bone marrow adipocytes support complete myeloid and lymphoid differentiation from human CD34 cells. Br J Haematol. 2004;127:344–7.

    Article  PubMed  Google Scholar 

  9. Di Mascio L, Voermans C, Uqoezwa M, Duncan A, Lu D, Wu J, et al. Identification of adiponectin as a novel hemopoietic stem cell growth factor. J Immunol. 2007;178:3511–20.

    Article  Google Scholar 

  10. Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A. 1996;93:14564–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Laharrague P. Human subcutaneous adipose cells support complete differentiation but not self-renewal of hematopoietic progenitors. J Cell Physiol. 2006;208:282–8.

    Article  PubMed  CAS  Google Scholar 

  12. •• Zhou BO, Yu H, Yue R, Zhao Z, Rios JJ, Naveiras O, et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol. 2017;19(8):891–903. This work demonstrates that bone marrow adipocytes can produce the Stem Cell Factor and maintain HSC survival and proliferation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Spindler TJ, Tseng AW, Zhou X, Adams GB. Adipocytic cells augment the support of primitive hematopoietic cells in vitro but have no effect in the bone marrow niche under homeostatic conditions. Stem Cells Dev. 2014;23(4):434–41.

    Article  PubMed  CAS  Google Scholar 

  14. Sanchez-Gurmaches J, Guertin DA. Adipocyte lineages: tracing back the origins of fat. Biochim Biophys Acta. 2014;1842:340–51.

    Article  PubMed  CAS  Google Scholar 

  15. Hardouin P, Rharass T, Lucas S. Bone marrow adipose tissue: to be or not to be a typical adipose tissue? Front Endocrinol. 2016;7:85.

    Article  Google Scholar 

  16. Devlin MJ. Why does starvation make bones fat? Am J Hum Biol. 2011;23(5):577–85.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tavassoli M. Differential response of bone marrow and extramedullary adipose cells to starvation. Experientia. 1974;30(4):424–5.

    Article  PubMed  CAS  Google Scholar 

  18. Cawthorn WP, Scheller EL, Learman BS, Parlee SD, Simon BR, Mori H, et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 2014;20:368–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Abella E, Feliu E, Granada I, Millá F, Oriol A, Ribera JM, et al. Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings. Am J Clin Pathol. 2002;118(4):582–8.

    Article  PubMed  CAS  Google Scholar 

  20. Cawthorn WP, Scheller EL, Parlee SD, Pham HA, Learman BS, Redshaw CM, et al. Expansion of bone marrow adipose tissue during caloric restriction is associated with increased circulating glucocorticoids and not with hypoleptinemia. Endocrinology. 2016;157(2):508–21.

    Article  PubMed  CAS  Google Scholar 

  21. Vande Berg BC, Malghem J, Lecouvet FE, Lambert M, Maldague BE. Distribution of serouslike bone marrow changes in the lower limbs of patients with anorexia nervosa: predominant involvement of the distal extremities. Am J Roentgenol. 1996;166(3):621–5.

    Article  CAS  Google Scholar 

  22. Shafat MS, Oellerich T, Mohr S, Robinson SD, Edwards DR, Marlein CR, et al. Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood. 2017;129(10):1320–32.

    Article  PubMed  CAS  Google Scholar 

  23. •• Cahu X, Calvo J, Poglio S, Prade N, Colsch B, Arcangeli ML, et al. Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia. Blood Adv. 2017;1(20):1760–72. This work, using murine bone marrow models of constitutive adipocyte-poor and –rich BM, demonstrates that these two microenvironments imprint niche-specific characteristics on T-ALL cells.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4(1–2):7–25.

    PubMed  CAS  Google Scholar 

  25. Tavassoli M. Marrow adipose cells. Histochemical identification of labile and stable components. Arch Pathol Lab Med. 1976;100:16–8.

    PubMed  CAS  Google Scholar 

  26. •• Scheller EL, Doucette CR, Learman BS, Cawthorn WP, Khandaker S, Schell B, et al. Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nat Commun. 2015;6:7808. This paper demonstrated that bone marrow adipocytes in the distal skeleton are different in morphology and function from the adipocytes located in the proximal bones, respectively part of the constitutive Marrow Adipose Tissue (cMAT) and regulated Marrow Adipose Tissue (rMAT). Adipocytes in the latter are smaller in size and their number can vary, depending on physiological condition of the organism.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Michael P. Gelatinous degeneration of the bone marrow. J Pathol. 1930;33(3):533–8.

    Article  CAS  Google Scholar 

  28. Böhm J. Gelatinous transformation of the bone marrow: the spectrum of underlying diseases. Am J Surg Pathol. 2000;24(1):56–65.

    Article  PubMed  Google Scholar 

  29. Crawford LJ, Peake R, Price S, Morris TC, Irvine AE. Adiponectin is produced by lymphocytes and is a negative regulator of granulopoiesis. J Leukoc Biol. 2010;88(4):807–11.

    Article  PubMed  CAS  Google Scholar 

  30. Yokota T, Meka CS, Kouro T, Medina KL, Igarashi H, Takahashi M, et al. Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells. J Immunol. 2003;171(10):5091–9.

    Article  PubMed  CAS  Google Scholar 

  31. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood. 2000;96(5):1723–32.

    PubMed  CAS  Google Scholar 

  32. Masamoto Y, Arai S, Sato T, Yoshimi A, Kubota N, Takamoto I, et al. Adiponectin enhances antibacterial activity of hematopoietic cells by suppressing bone marrow inflammation. Immunity. 2016;44(6):1422–33.

    Article  PubMed  CAS  Google Scholar 

  33. Masamoto Y, Arai S, Sato T, Kubota N, Takamoto I, Kadowaki T, et al. Adiponectin enhances quiescence exit of murine hematopoietic stem cells and hematopoietic recovery through mTORC1 potentiation. Stem Cells. 2017;35(7):1835–48.

    Article  PubMed  CAS  Google Scholar 

  34. Lin FY, Wu HC, Cheng KC, Tung CL, Chang CP, Feng YH. Adiponectin is down-regulated in bone marrow interstitial fluid in hematological malignancy. Int J Hematol. 2015;102(3):312–7.

    Article  PubMed  CAS  Google Scholar 

  35. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–81.

    Article  PubMed  CAS  Google Scholar 

  36. Broudy VC. Stem cell factor and hematopoiesis. Blood. 1997;90(4):1345–64.

    PubMed  CAS  Google Scholar 

  37. Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A. 1996;93:14564–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Camacho V, McClearn V, Patel S, Welner RS. Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment. Int J Hematol. 2017;105(5):566–77.

    Article  PubMed  CAS  Google Scholar 

  39. Robles H, Park S, Joens MS, Fitzpatrick JAJ, Craft CS and Scheller EL. Characterization of the bone marrow adipocyte niche with three-dimensional electron microscopy. Bone 2018:S8756–3282(18)30020–30026.

  40. Manabe Y, Toda S, Miyazaki K, Sugihara H. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions. J Pathol. 2003;201(2):221–8.

    Article  PubMed  Google Scholar 

  41. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498–503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metastasis. 2015;32(4):353–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Sheng X, Tucci J, Parmentier JH, Ji L, Behan JW, Heisterkamp N, et al. Adipocytes cause leukemia cell resistance to daunorubicin via oxidative stress response. Oncotarget. 2016;7(45):73147–59.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Behan JW, Yun JP, Proektor MP, Ehsanipour EA, Arutyunyan A, Moses AS, et al. Adipocytes impair leukemia treatment in mice. Cancer Res. 2009;69(19):7867–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Ehsanipour EA, Sheng X, Behan JW, Wang X, Butturini A, Avramis VI, et al. Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine. Cancer Res. 2013;73(10):2998–3006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Liu Z, Xu J, He J, Liu H, Lin P, Wan X, et al. Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation. Oncotarget. 2015;6(33):34329–41.

    PubMed  PubMed Central  Google Scholar 

  47. Lu W, Wan Y, Li Z, Zhu B, Yin C, Liu H, et al. Growth differentiation factor 15 contributes to marrow adipocyte remodeling in response to the growth of leukemic cells Growth differentiation factor 15 contributes to marrow adipocyte remodeling in response to the growth of leukemic cells. J Exp Clin Cancer Res. 2018;37:66.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453:783–7.

    Article  PubMed  CAS  Google Scholar 

  49. •• Boyd AL, Reid JC, Salci KR, Aslostovar L, Benoit YD, Shapovalova Z, et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol. 2017;19(11):1336–47. This work shows that AML disrupts the adipocytic niche in the bone marrow, leading to imbalanced regulation of endogenous haematopoietic stem and progenitor cells and resulting in impaired myelo-erythroid maturation.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Daniel Naveed Tavakol for his editing help.

We also thank the “BONEAhead” initiative for making our collaboration possible.

Author information

Authors and Affiliations

  1. Clinica di Ematologia, Dipartimento Scienze Cliniche e Molecolari, Università Politecnica Marche, Via Tronto 10, 60126, Ancona, Italy

    Domenico Mattiucci & Antonella Poloni

  2. Laboratory of Regenerative Hematopoiesis, School of Life Sciences, Swiss Experimental Cancer Research Institute (ISREC) and Institute of Bioengineering (IBI), École Polytechnique Fédérale de Lausanne (EPFL) & Hematology Division, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Olaia Naveiras

Authors
  1. Domenico Mattiucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olaia Naveiras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonella Poloni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonella Poloni.

Ethics declarations

Conflict of Interest

Domenico Mattiucci and Antonella Poloni declare no conflicts of interest; Olaia Naveiras reports having a related patent US13264423 issued.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Molecular Biology of Bone Marrow Fat Adiposity

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mattiucci, D., Naveiras, O. & Poloni, A. Bone Marrow “Yellow” and “Red” Adipocytes”: Good or Bad Cells?. Curr Mol Bio Rep 4, 117–122 (2018). https://doi.org/10.1007/s40610-018-0098-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40610-018-0098-6

Keywords

Search

Navigation