Marrow Adiposity and Hematopoiesis in Aging and Obesity: Exercise as an Intervention
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Purpose of Review
Changes in the bone marrow microenvironment, which accompany aging and obesity, including increased marrow adiposity, can compromise hematopoiesis. Here, we review deleterious shifts in molecular, cellular, and tissue activity and consider the potential of exercise to slow degenerative changes associated with aging and obesity.
While bone marrow hematopoietic stem cells (HSC) are increased in frequency and myeloid-biased with age, the effect of obesity on HSC proliferation and differentiation remains controversial. HSC from both aged and obese environment have reduced hematopoietic reconstitution capacity following bone marrow transplant. Increased marrow adiposity affects HSC function, causing upregulation of myelopoiesis and downregulation of lymphopoiesis. Exercise, in contrast, can reduce marrow adiposity and restore hematopoiesis.
The impact of marrow adiposity on hematopoiesis is determined mainly through correlations. Mechanistic studies are needed to determine a causative relationship between marrow adiposity and declines in hematopoiesis, which could aid in developing treatments for conditions that arise from disruptions in the marrow microenvironment.
KeywordsBone marrow microenvironment Lymphopoiesis Myelopoiesis Exercise Whole-body vibration
This work was supported by National Institute of Health through National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR-43498 and National Institute of Biomedical Imaging and Bioengineering grant EB-14351.
Compliance with Ethical Standards
Conflict of Interest
Janet Rubin, Vihitaben Patel, and M. Ete Chan declare no conflict of interest. Clinton Rubin has authored patents related to the use of mechanical signals to bias stem cell fate and mechanical regulation of metabolic diseases. He is also a Founder of Marodyne Medical. Other authors have nothing to disclose.
Human and Animal Rights and Informed Consent
All animal and human studies referred to herein, that were performed by any/all of the authors, were reviewed and approved by the university (SBU and/or UNC) human/animal user committees. In addition, any of the human studies referred to, performed by Dr. C. Rubin, were done with informed consent of the subjects.
Papers of particular interest, published recently, have been highlighted as: • Of importance ••Of major importance
- 3.Luu YK, Capilla E, Rosen CJ, Gilsanz V, Pessin JE, Judex S, et al. Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity. J Bone Miner Res. 2009;24(1):50–61. https://doi.org/10.1359/jbmr.080817.CrossRefPubMedGoogle Scholar
- 4.Alvarez-Viejo M, Menendez-Menendez Y, Blanco-Gelaz MA, Ferrero-Gutierrez A, Fernandez-Rodriguez MA, Gala J, et al. Quantifying mesenchymal stem cells in the mononuclear cell fraction of bone marrow samples obtained for cell therapy. Transplant Proc. 2013;45(1):434–9. https://doi.org/10.1016/j.transproceed.2012.05.091.CrossRefPubMedGoogle Scholar
- 5.•• Patel VS, Chan ME, Pagnotti GM, Frechette DM, Rubin J, Rubin CT. Incorporating refractory period in mechanical stimulation mitigates obesity-induced adipose tissue dysfunction in adult mice. Obesity (Silver Spring). 2017;25(10):1745–53. https://doi.org/10.1002/oby.21958. This study demonstrates that obesity leads to systemic chronic inflammatory state by inducing increased infiltration of immune cells in the adipose tissue, which is restored via whole-body vibration. In addition, this study emphasizes that in adults, whole-body vibration treatment is only effective when it is separated with a rest period. CrossRefGoogle Scholar
- 9.Rubin CT, Capilla E, Luu YK, Busa B, Crawford H, Nolan DJ, et al. Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc Natl Acad Sci U S A. 2007;104(45):17879–84. https://doi.org/10.1073/pnas.0708467104.CrossRefPubMedPubMedCentralGoogle Scholar
- 12.•• Adler BJ, Green DE, Pagnotti GM, Chan ME, Rubin CT. High fat diet rapidly suppresses B lymphopoiesis by disrupting the supportive capacity of the bone marrow niche. PLoS One. 2014;9(3):e90639. https://doi.org/10.1371/journal.pone.0090639. This paper demonstrates that high-fat diet leads to increase in marrow adiposity, paralleled by reduced B lymphopoiesis and increased myelopoiesis. CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Thon JN, Italiano JE. Platelet formation. Semin Hematol. 2010;47(3):220–6. https://doi.org/10.1053/j.seminhematol.2010.03.005.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Janssen WJ, Bratton DL, Jakubzick CV, Henson PM. Myeloid cell turnover and clearance. Microbiol Spectr. 2016;4(6). https://doi.org/10.1128/microbiolspec.MCHD-0005-2015.
- 29.Majumdar MK, Thiede MA, Haynesworth SE, Bruder SP, Gerson SL. Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages. J Hematother Stem Cell Res. 2000;9(6):841–8. https://doi.org/10.1089/152581600750062264.CrossRefPubMedGoogle Scholar
- 30.Mishima S, Nagai A, Abdullah S, Matsuda C, Taketani T, Kumakura S, et al. Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent. Eur J Haematol. 2010;84(6):538–46. https://doi.org/10.1111/j.1600-0609.2010.01419.x.CrossRefPubMedGoogle Scholar
- 31.Carrancio S, Blanco B, Romo C, Muntion S, Lopez-Holgado N, Blanco JF, et al. Bone marrow mesenchymal stem cells for improving hematopoietic function: an in vitro and in vivo model. Part 2: effect on bone marrow microenvironment. PLoS One. 2011;6(10):e26241. https://doi.org/10.1371/journal.pone.0026241.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15(1):42–9. https://doi.org/10.1038/nm.1905.CrossRefPubMedGoogle Scholar
- 34.Roddy GW, Oh JY, Lee RH, Bartosh TJ, Ylostalo J, Coble K, et al. Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-alpha stimulated gene/protein 6. Stem Cells. 2011;29(10):1572–9. https://doi.org/10.1002/stem.708.CrossRefPubMedGoogle Scholar
- 37.Marks SC Jr, Mackay CA, Jackson ME, Larson EK, Cielinski MJ, Stanley ER, et al. The skeletal effects of colony-stimulating factor-1 in toothless (osteopetrotic) rats: persistent metaphyseal sclerosis and the failure to restore subepiphyseal osteoclasts. Bone. 1993;14(4):675–80.CrossRefPubMedGoogle Scholar
- 49.Scheller EL, Doucette CR, Learman BS, Cawthorn WP, Khandaker S, Schell B, et al. Corrigendum: region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nat Commun. 2016;7:13775. https://doi.org/10.1038/ncomms13775.CrossRefPubMedPubMedCentralGoogle Scholar
- 51.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(2):368–75. https://doi.org/10.1016/j.cmet.2014.06.003.CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Pearce DJ, Anjos-Afonso F, Ridler CM, Eddaoudi A, Bonnet D. Age-dependent increase in side population distribution within hematopoiesis: implications for our understanding of the mechanism of aging. Stem Cells. 2007;25(4):828–35. https://doi.org/10.1634/stemcells.2006-0405.CrossRefPubMedGoogle Scholar
- 58.Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20(6):771–84.e6. https://doi.org/10.1016/j.stem.2017.02.009.CrossRefPubMedPubMedCentralGoogle Scholar
- 60.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 hematopoietic stem cell numbers and cytokine levels with aging. J Anat. 2011;219(5):574–81. https://doi.org/10.1111/j.1469-7580.2011.01423.x.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Reinisch A, Etchart N, Thomas D, Hofmann NA, Fruehwirth M, Sinha S, et al. Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation. Blood. 2015;125(2):249–60. https://doi.org/10.1182/blood-2014-04-572255.CrossRefPubMedPubMedCentralGoogle Scholar
- 63.do Carmo LS, Rogero MM, Paredes-Gamero EJ, Nogueira-Pedro A, Xavier JG, Cortez M, et al. A high-fat diet increases interleukin-3 and granulocyte colony-stimulating factor production by bone marrow cells and triggers bone marrow hyperplasia and neutrophilia in Wistar rats. Exp Biol Med (Maywood). 2013;238(4):375–84. https://doi.org/10.1177/1535370213477976.CrossRefGoogle Scholar
- 69.Nteeba J, Ortinau LC, Perfield JW 2nd, Keating AF. Diet-induced obesity alters immune cell infiltration and expression of inflammatory cytokine genes in mouse ovarian and peri-ovarian adipose depot tissues. Mol Reprod Dev. 2013;80(11):948–58. https://doi.org/10.1002/mrd.22231.CrossRefPubMedGoogle Scholar
- 70.Caer C, Rouault C, Le Roy T, Poitou C, Aron-Wisnewsky J, Torcivia A, et al. Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue. Sci Rep. 2017;7(1):3000. https://doi.org/10.1038/s41598-017-02660-w.CrossRefPubMedPubMedCentralGoogle Scholar
- 71.Doucette CR, Horowitz MC, Berry R, MacDougald OA, Anunciado-Koza R, Koza RA, et al. A high fat diet increases bone marrow adipose tissue (MAT) but does not Alter trabecular or cortical bone mass in C57BL/6J mice. J Cell Physiol. 2015;230(9):2032–7. https://doi.org/10.1002/jcp.24954.CrossRefPubMedPubMedCentralGoogle Scholar
- 73.•• Styner M, Thompson WR, Galior K, Uzer G, Wu X, Kadari S, et al. Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise. Bone. 2014;64:39–46. https://doi.org/10.1016/j.bone.2014.03.044. This paper demonstrates that high-fat diet leads to increased marrow adiposity, which gets suppressed by exercise. CrossRefPubMedPubMedCentralGoogle Scholar
- 75.Caselli A, Olson TS, Otsuru S, Chen X, Hofmann TJ, Nah HD, et al. IGF-1-mediated osteoblastic niche expansion enhances long-term hematopoietic stem cell engraftment after murine bone marrow transplantation. Stem Cells. 2013;31(10):2193–204. https://doi.org/10.1002/stem.1463.CrossRefPubMedGoogle Scholar
- 77.Liang X, Su YP, Kong PY, Zeng DF, Chen XH, Peng XG, et al. Human bone marrow mesenchymal stem cells expressing SDF-1 promote hematopoietic stem cell function of human mobilised peripheral blood CD34+ cells in vivo and in vitro. Int J Radiat Biol. 2010;86(3):230–7. https://doi.org/10.3109/09553000903422555.CrossRefPubMedGoogle Scholar
- 78.Lapidot T, Kollet O. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia. 2002;16(10):1992–2003. https://doi.org/10.1038/sj.leu.2402684.CrossRefPubMedGoogle Scholar
- 80.Holt V, Caplan AI, Haynesworth SE. Identification of a subpopulation of marrow MSC-derived medullary adipocytes that express osteoclast-regulating molecules: marrow adipocytes express osteoclast mediators. PLoS One. 2014;9(10):e108920. https://doi.org/10.1371/journal.pone.0108920.CrossRefPubMedPubMedCentralGoogle Scholar
- 81.• Kennedy DE, Knight KL. Inhibition of B lymphopoiesis by adipocytes and IL-1-producing myeloid-derived suppressor cells. J Immunol. 2015;195(6):2666–74. https://doi.org/10.4049/jimmunol.1500957. This study demonstrates that MAT-induced depletion in B lymphopoiesis is mediated by secretion of IL-1. CrossRefPubMedPubMedCentralGoogle Scholar
- 82.• Huang JY, Zhou QL, Huang CH, Song Y, Sharma AG, Liao Z, et al. Neutrophil elastase regulates emergency myelopoiesis preceding systemic inflammation in diet-induced obesity. J Biol Chem. 2017;292(12):4770–6. https://doi.org/10.1074/jbc.C116.758748. This study demonstrates that obesity-induced myeloid bias is mediated via secretion of neutrophil elastase. CrossRefPubMedGoogle Scholar
- 87.• Styner M, Pagnotti GM, McGrath C, Wu X, Sen B, Uzer G, et al. Exercise decreases marrow adipose tissue through ß-oxidation in obese running mice. J Bone Miner Res. 2017; https://doi.org/10.1002/jbmr.3159. This study demonstrates that reduction in high-fat diet-induced accumulation in marrow adiposity during exercise is mediated via basal lyposis and β-oxidation, which is partially mediated by perilipin 3.
- 88.Shen W, Chen J, Gantz M, Punyanitya M, Heymsfield SB, Gallagher D, et al. MRI-measured pelvic bone marrow adipose tissue is inversely related to DXA-measured bone mineral in younger and older adults. Eur J Clin Nutr. 2012;66(9):983–8. https://doi.org/10.1038/ejcn.2012.35.CrossRefPubMedPubMedCentralGoogle Scholar
- 91.Covington JD, Noland RC, Hebert RC, Masinter BS, Smith SR, Rustan AC, et al. Perilipin 3 differentially regulates skeletal muscle lipid oxidation in active, sedentary, and type 2 diabetic males. J Clin Endocrinol Metab. 2015;100(10):3683–92. https://doi.org/10.1210/jc.2014-4125.CrossRefPubMedPubMedCentralGoogle Scholar
- 92.Patel S, Yang W, Kozusko K, Saudek V, Savage DB. Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis. Proc Natl Acad Sci U S A. 2014;111(25):9163–8. https://doi.org/10.1073/pnas.1318791111.CrossRefPubMedPubMedCentralGoogle Scholar
- 93.Trudel G, Coletta E, Cameron I, Belavy DL, Lecompte M, Armbrecht G, et al. Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men. J Appl Physiol. 2012;112(11):1824–31. https://doi.org/10.1152/japplphysiol.00029.2012.CrossRefPubMedGoogle Scholar