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Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment
Open accessAbstract
Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow. 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 aplasia. 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 adipocytes, and in mice treated with the peroxisome proliferator-activated receptor-gamma inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis, 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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“A similar fatty deterioration of the bone marrow microenvironment occurs (41)”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [41]
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“Moreover, adipocytes have been described to secrete mediators suppressing hematopoiesis and upholding a proinflammatory environment such as TNF-a.51”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [51]
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“similar to that observed in bone marrow, where adiposity was found to correlate inversely with the functionality of hematopoietic stem ⁄ progenitor cells (Naveiras et al., 2009).”
BackgroundResultLuo, Y., Chen, G., Hannemann, N., Ipseiz, N., Krönke, G., Bäuerle, T., Munos, L., Wirtz, S. J., Schett, G. A., & Bözec, A. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.08.020 · Cited by 201
“Treatment with PPARg antagonist BADGE, known to increase osteoblastogenesis but decrease BM adiposity (Duque et al., 2013; Naveiras et al., 2009), normalized PPARg2 and leptin levels and reversed the altered balance between OBL and adipocyte in HFD-treated mice in vivo.”
BackgroundA Revised Perspective of Skeletal Stem Cell Biology
Ambrosi, T. H., Longaker, M. T., & Chan, C. K. F. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00189 · Cited by 196
Pontikoglou, C. G., Deschaseaux, F., Sensebé, L., & Papadaki, H. Α. (2011) · Stem Cell Reviews and Reports · doi:10.1007/s12015-011-9228-8 · Cited by 207
“Nevertheless there is evidence [129] that adipocytes exert an inhibitory effect on hematopoiesis, which seems to involve prevention of hematopoietic progenitor expansion, while preserving HSC pool.”
BackgroundVascular Wall Progenitor Cells in Health and Disease
Psaltis, P. J., & Simari, R. D. (2015) · Circulation Research · doi:10.1161/circresaha.116.305368 · Cited by 198
“Adipocytes are already known to contribute to stem cell niches in other tissues, including as negative regulators of BM hematopoiesis.(124) Although still speculative, it is easy to extrapolate that perivascular adipocytes might impart some of their influence on vascular wall health and disease through their close pro…”
BackgroundThe fat and the bad: Mature adipocytes, key actors in tumor progression and resistance
Duong, M. N., Geneste, A., Fallone, F., Li, X., Dumontet, C., & Muller, C. (2017) · Oncotarget · doi:10.18632/oncotarget.18038 · Cited by 198
Horowitz, M., Berry, R., Holtrup, B., Sebo, Z. L., Nelson, T., Fretz, J. A., Lindskog, D., Kaplan, J. L., Ables, G., Rodeheffer, M. S., et al. (2017) · Adipocyte · doi:10.1080/21623945.2017.1367881 · Cited by 172
“to 3-fold in BM from adipocyte-enriched tail vertebrae compared with BM from thoracic vertebrae.(3) Additionally, preventing BM adipogenesis following lethal irradiation and bone marrow reconstitution using genetic or pharmacologic methods results in accelerated hematopoietic recovery.”
BackgroundInfluentialUpdate on the effects of microgravity on the musculoskeletal system
Juhl, O. J., Buettmann, E. G., Friedman, M. A., DeNapoli, R. C., Hoppock, G. A., & Donahue, H. J. (2021) · npj Microgravity · doi:10.1038/s41526-021-00158-4 · Cited by 204
Scheller, E., Troiano, N., Vanhoutan, J. N., Bouxsein, M., Fretz, J. A., Xi, Y., Nelson, T., Katz, G., Berry, R., Church, C., et al. (2014) · Methods in Enzymology · doi:10.1016/b978-0-12-411619-1.00007-0 · Cited by 173
“This historical finding has since been reobserved in mice and used as the basis for studies of MAT regulation of bone formation and hematopoiesis (Naveiras et al., 2009; Wronski, Smith, & Jee, 1981).”
MethodHematopoiesis and Cardiovascular Disease
Poller, W. C., Nahrendorf, M., & Świrski, F. K. (2020) · Circulation Research · doi:10.1161/circresaha.120.315895 · Cited by 191
Adipocytes Impair Leukemia Treatment in Mice
Behan, J. W., Yun, J. P., Proektor, M. P., Ehsanipour, E. A., Arutyunyan, A., Moses, A. S., Avramis, V. I., Louie, S. G., Butturini, A. M., Heisterkamp, N., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0800 · Cited by 190
“This complements recent studies that seem to suggest that adipocytes impair the proliferation of normal hematopoietic cells (29), while they support the growth of malignant cells such as multiple myeloma cells (30).”
ResultNishikawa, K., Nakashima, T., Takeda, S., Isogai, M., Hamada, M., Kimura, A., Kodama, T., Yamaguchi, A., Owen, M. J., Takahashi, S., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42528 · Cited by 181
The bone marrow microenvironment – Home of the leukemic blasts
Shafat, M. S., Gnaneswaran, B., Bowles, K. M., & Rushworth, S. A. (2017) · Blood Reviews · doi:10.1016/j.blre.2017.03.004 · Cited by 185
Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells
Guidi, N., Saçma, M., Ständker, L., Soller, K., Marka, G., Eiwen, K., Weiss, J. M., Kirchhoff, F., Weil, T., Cancelas, J. A., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201694969 · Cited by 173
“Changes in the niche composition or function upon aging involve decreased bone formation, enhanced adipogenesis and changes in extracellular matrix (ECM) components (Calvi et al , 2003; Zhang et al , 2003; Naveiras et al , 2009; Geiger et al , 2013).”
Marrow fat metabolism is linked to the systemic energy metabolism
Lecka‐Czernik, B. (2011) · Bone · doi:10.1016/j.bone.2011.06.032 · Cited by 168
“Recent evidence indicates that the support for hematopoiesis is provided rather by adipo-osteogenic progenitors, which are essential for the maintenance of hematopoietic niche within the marrow [66].”
Regulation of Hematopoiesis and Osteogenesis by Blood Vessel–Derived Signals
Ramasamy, S. K., Kusumbe, A. P., Itkin, T., Gur‐Cohen, S., Lapidot, T., & Adams, R. H. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-124936 · Cited by 176
“This claim is further supported by the fact that adipocytes, which negatively regulate BM HSC maintenance, become more abundant in the central BM in adulthood and in aging (Naveiras et al. 2009).”
BackgroundCortez, M., do Carmo, L. S., Rogero, M. M., Borelli, P., & Fock, R. A. (2012) · Inflammation · doi:10.1007/s10753-012-9557-z · Cited by 174
“Adipocytes, conversely, suppress hematopoiesis under homeostatic conditions and particularly under stressed conditions [14].”
BackgroundObesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice
Halade, G. V., Jamali, A. E., Williams, P. J., Fajardo, R. J., & Fernandes, G. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.09.014 · Cited by 169
“It has been suggested that increasing amounts of fat in the BM microenvironment (Naveiras et al., 2009) may affect bone turnover, through both the inhibition of osteoblast function and increased osteoclast differentiation/activation (Oh et al.”
InfluentialHematopoietic Stem Cell Niche in Health and Disease
Hoggatt, J., Kfoury, Y. S., & Scadden, D. T. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044414 · Cited by 168
Myeloid malignancies and the microenvironment
Korn, C., & Méndez‐Ferrer, S. (2016) · Blood · doi:10.1182/blood-2016-09-670224 · Cited by 170
“Adipocyte accumulation in aplastic BM might compromise niche function by negatively influencing hematopoietic recovery after myeloablation.(122) Therefore, the damage inflicted by chemotherapy in the BM microenvironment can interfere with normal hematopoiesis and eventually result in BM failure.”
Green, D. E., & Rubin, C. T. (2014) · Bone · doi:10.1016/j.bone.2014.02.018 · Cited by 175
“Adipocytes on the other hand have shown to be negative regulators of hematopoietic progenitors cells [56].”
BackgroundInfluentialNoncanonical Wnt signaling in vertebrate development, stem cells, and diseases
Sugimura, R., & Li, L. (2010) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.20195 · Cited by 174
Roles of nonmyogenic mesenchymal progenitors in pathogenesis and regeneration of skeletal muscle
Uezumi, A., Ikemoto‐Uezumi, M., & Tsuchida, K. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00068 · Cited by 171
Deng, P., Yuan, Q., Cheng, Y., Li, J., Liu, Z., Liu, Y., Li, Y., Su, T., Wang, J., Salvo, M. E., et al. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.01.010 · Cited by 165
Nishio, M., Yoneshiro, T., Nakahara, M., Suzuki, S., Saeki, K., Hasegawa, M., Kawai, Y., Akutsu, H., Umezawa, A., Yasuda, K., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.08.001 · Cited by 169
“…regarding the effects of ‘‘BM adipocyte’’ on the committed HPCs: some reports showed its capacity to support lymphopoiesis (Gimble et al., 1990) and granulopoiesis (Gimble et al., 1992), while others showed its inhibiting effects for hematopoiesis (Ookura et al., 2007, Naveiras et al., 2009).”
BackgroundHematopoietic Stem Cell and Its Bone Marrow Niche
Yu, V. W. C., & Scadden, D. T. (2016) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2016.01.009 · Cited by 179
Global Remodeling of the Vascular Stem Cell Niche in Bone Marrow of Diabetic Patients
Spinetti, G., Cordella, D., Fortunato, O., Sangalli, E., Losa, S., Gotti, A., Carnelli, F., Rosa, F., Riboldi, S., Sessa, F., et al. (2012) · Circulation Research · doi:10.1161/circresaha.112.300598 · Cited by 157
“Although additional investigation is needed to interpret the relationship between fatty infiltration of the marrow and obesity, evidence indicates that BM adipocytes could contribute to inhibit hematopoiesis in an obese model of T2DM.48 We found a direct correlation between vascular rarefaction and marrow remodeling,…”
BackgroundCharacterization of age-related gene expression profiling in bone marrow and epididymal adipocytes
Liu, L.-F., Shen, W., Ueno, M., Patel, S., & Kraemer, F. B. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-212 · Cited by 153
Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise
Styner, M., Thompson, W. R., Galior, K. D., Uzer, G., Wu, X., Kadari, S., Case, N. D., Xie, Z., Sen, B., Romaine, A., et al. (2014) · Bone · doi:10.1016/j.bone.2014.03.044 · Cited by 155
“In our study we were able to visualize increases in MAT in the metaphysis extending into the diaphysis during high fat feeding, correlating with histology and other data in the literature, indicating that marrow adipose normally shares space within the trabecular bone [9, 31].”
Metadata
- Authors
- Naveiras, O., Nardi, V., Wenzel, P. L., Hauschka, P. V., Fahey, F., & Daley, G. Q.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Boston Children's Hospital (US)
- Corresponding author
- Daley, George Q.
- Venue
- Nature
- Published
- 2009-06-10
- Volume
- 460
- Issue
- 7252
- Pages
- 259-263
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2831539
- OpenAlex
- W2100140007
- Cited by
- 1,129
- References
- 31
- Citations by year
- 2026: 22 · 2025: 49 · 2024: 64 · 2023: 68 · 2022: 62 · 2021: 84 · 2020: 96 · 2019: 71 · 2018: 71 · 2017: 94 · 2016: 69 · 2015: 65 · 2014: 59 · 2013: 69 · 2012: 67
- FWCI
- 39.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DP1OD000256)
- National Heart, Lung, and Blood Institute (T32HL007623)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK059279, R01DK070055)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- bone marrow adipocytes, hematopoiesis, hematopoietic stem cells, hematopoietic progenitor cells, adipogenesis, bone marrow transplantation, hematopoietic recovery, DGEBA, PPARγ
- MeSH terms
- Bisphenol A Compounds, Animals, Benzhydryl Compounds, Bone Marrow Cells, Cell Line, Epoxy Compounds, Femur, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Mice, Inbred C57BL, Osteogenesis, Spine, Tail, Thorax, Tibia, Bone Marrow Transplantation, Stromal Cells, Adipocytes, Adiposity, Adipogenesis, Mice
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