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Chronic variable stress activates hematopoietic stem cells

Nature Medicine volume 20, pages 754–758 (2014)Cite this article

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Abstract

Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis1,2. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex3,4. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe−/− mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.

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Figure 1: Chronic stress increases proliferation of HSPCs in the bone marrow.
Figure 2: Stress leads to increased bone marrow hematopoietic progenitor cell proliferation.
Figure 3: Stress-induced sympathetic nervous system signaling regulates the proliferation of bone marrow HSCs via CXCL12.
Figure 4: Chronic stress increases inflammation in mouse atherosclerotic plaques.

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References

  1. Black, P.H. The inflammatory response is an integral part of the stress response: implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav. Immun. 17, 350–364 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Rosengren, A. et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 364, 953–962 (2004).

    Article  PubMed  Google Scholar 

  3. Glaser, R. & Kiecolt-Glaser, J.K. Stress-induced immune dysfunction: implications for health. Nat. Rev. Immunol. 5, 243–251 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Powell, N.D. et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc. Natl. Acad. Sci. USA 110, 16574–16579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cohen, S., Kamarck, T. & Mermelstein, R. A global measure of perceived stress. J. Health Soc. Behav. 24, 385–396 (1983).

    Article  CAS  PubMed  Google Scholar 

  6. Lesage, F.X. & Berjot, S. Validity of occupational stress assessment using a visual analogue scale. Occup. Med. (Lond.) 61, 434–436 (2011).

    Article  CAS  Google Scholar 

  7. Schweizer, M.C., Henniger, M.S. & Sillaber, I. Chronic mild stress (CMS) in mice: of anhedonia, 'anomalous anxiolysis' and activity. PLoS ONE 4, e4326 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Nollet, M., Guisquet, A.M. & Belzung, C. Models of depression: unpredictable chronic mild stress in mice. Curr. Protoc. Pharmacol. 61, 5.65 (2013).

    Google Scholar 

  9. Yalcin, I., Aksu, F. & Belzung, C. Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol. Eur. J. Pharmacol. 514, 165–174 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Kiel, M.J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Szilvassy, S.J., Humphries, R.K., Lansdorp, P.M., Eaves, A.C. & Eaves, C.J. Quantitative assay for totipotent reconstituting hematopoietic stem cells by a competitive repopulation strategy. Proc. Natl. Acad. Sci. USA 87, 8736–8740 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Essers, M.A. et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Baldridge, M.T., King, K.Y., Boles, N.C., Weksberg, D.C. & Goodell, M.A. Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection. Nature 465, 793–797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lo Celso, C., Lin, C.P. & Scadden, D.T. In vivo imaging of transplanted hematopoietic stem and progenitor cells in mouse calvarium bone marrow. Nat. Protoc. 6, 1–14 (2011).

    Article  PubMed  CAS  Google Scholar 

  16. Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P.S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

    Article  PubMed  CAS  Google Scholar 

  17. Spiegel, A. et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat. Immunol. 8, 1123–1131 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Lucas, D. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19, 695–703 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zigmond, R.E. & Ben-Ari, Y. Electrical stimulation of preganglionic nerve increases tyrosine hydroxylase activity in sympathetic ganglia. Proc. Natl. Acad. Sci. USA 74, 3078–3080 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Morrison, S.J. & Scadden, D.T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ding, L. & Morrison, S.J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eash, K.J., Means, J.M., White, D.W. & Link, D.C. CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions. Blood 113, 4711–4719 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tzeng, Y.S. et al. Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood 117, 429–439 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Nie, Y., Han, Y.C. & Zou, Y.R. CXCR4 is required for the quiescence of primitive hematopoietic cells. J. Exp. Med. 205, 777–783 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Libby, P., Ridker, P.M. & Hansson, G.K. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Randolph, G.J. The fate of monocytes in atherosclerosis. J. Thromb. Haemost. 7 (suppl. 1), 28–30 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rader, D.J. & Daugherty, A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 451, 904–913 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Swirski, F.K. & Nahrendorf, M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339, 161–166 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Moore, K.J. & Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341–355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Libby, P. Mechanisms of acute coronary syndromes and their implications for therapy. N. Engl. J. Med. 368, 2004–2013 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Adamsson Eryd, S., Smith, J.G., Melander, O., Hedblad, B. & Engstrom, G. Incidence of coronary events and case fatality rate in relation to blood lymphocyte and neutrophil counts. Arterioscler. Thromb. Vasc. Biol. 32, 533–539 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Kaplan, J.R. et al. Social stress and atherosclerosis in normocholesterolemic monkeys. Science 220, 733–735 (1983).

    Article  CAS  PubMed  Google Scholar 

  35. Gu, H., Tang, C., Peng, K., Sun, H. & Yang, Y. Effects of chronic mild stress on the development of atherosclerosis and expression of toll-like receptor 4 signaling pathway in adolescent apolipoprotein E knockout mice. J. Biomed. Biotechnol. 2009, 613879 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Bernberg, E., Ulleryd, M.A., Johansson, M.E. & Bergstrom, G.M. Social disruption stress increases IL-6 levels and accelerates atherosclerosis in Apoe−/− mice. Atherosclerosis 221, 359–365 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Wilbert-Lampen, U. et al. Cardiovascular events during World Cup soccer. N. Engl. J. Med. 358, 475–483 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Wantha, S. et al. Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ. Res. 112, 792–801 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Tall, A.R., Yvan-Charvet, L., Westerterp, M. & Murphy, A.J. Cholesterol efflux: a novel regulator of myelopoiesis and atherogenesis. Arterioscler. Thromb. Vasc. Biol. 32, 2547–2552 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Encinas, J.M et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8, 566–579 (2007).

    Article  CAS  Google Scholar 

  42. Purton, L.E. & Scadden, D.T. Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell 1, 263–270 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Hu, Y. & Smyth, G.K. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J. Immunol. Methods 347, 70–78 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kobayashi, M. & Srour, E.F. Regulation of murine hematopoietic stem cell quiescence by Dmtf1. Blood 118, 6562–6571 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shi, C. et al. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating Toll-like receptor ligands. Immunity 34, 590–601 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Westerterp, M. et al. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux pathways. Cell Stem Cell 11, 195–206 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schepers, K. et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 13, 285–299 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Seimon, T.A. et al. Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice. J. Clin. Invest. 119, 886–898 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zaheer, A. et al. In vivo near-infrared fluorescence imaging of osteoblastic activity. Nat. Biotechnol. 19, 1148–1154 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Nahrendorf, M. et al. Hybrid PET-optical imaging using targeted probes. Proc. Natl. Acad. Sci. USA 107, 7910–7915 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the team at the Center for Systems Biology Mouse Imaging Program, especially J. Truelove and D. Jeon, for help with imaging, M. Stein, I. Neudorfer and F. Meixner for help with the clinical study and L. Prickett-Rice, K. Folz-Donahue, M. Weglarz, M. Waring and A. Chicoine for assistance with cell sorting. We thank P. Frenette (Albert Einstein College of Medicine) and B. Lowell (Beth Israel Deaconess Medical Center) for providing Adrb3−/− mice and G. Enikolopov (Cold Spring Harbor Laboratory) for providing nestin-GFP mice. We thank the ICU team at the University Hospital Freiburg, Germany. This work was funded in part by US National Institutes of Health grants R01-HL114477, R01-HL117829 and R01-HL096576 (to M.N.) and grant HHSN268201000044C (to R.W.). T.H. and H.B.S. are funded by the Deutsche Forschungsgemeinschaft (HE-6382/1-1 to T.H. and SA1668/2-1 to H.B.S.).

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Author notes

  1. Timo Heidt and Hendrik B Sager: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Timo Heidt, Hendrik B Sager, Gabriel Courties, Partha Dutta, Yoshiko Iwamoto, Alex Zaltsman, Charles P Lin, Claudio Vinegoni, Filip K Swirski, Ralph Weissleder & Matthias Nahrendorf

  2. Department of Cardiology and Angiology I, University Heart Center, Freiburg, Germany

    Constantin von zur Muhlen & Christoph Bode

  3. Division of Psychiatry and Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

    Gregory L Fricchione & John Denninger

  4. Benson-Henry Institute for Mind Body Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

    Gregory L Fricchione & John Denninger

  5. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Peter Libby

  6. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

    Ralph Weissleder

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Contributions

T.H. and H.B.S. performed experiments, collected, analyzed and discussed data and contributed to writing the manuscript. G.C., P.D., A.Z. and Y.I. performed experiments and collected, analyzed and discussed data. C.v.z.M., C.B., C.P.L., J.D., G.L.F., C.V., P.L., F.K.S. and R.W. conceived experiments and discussed results and strategy. M.N. managed and designed the study and wrote the manuscript, which was revised and approved by all authors.

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Correspondence to Matthias Nahrendorf.

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The authors declare no competing financial interests.

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Heidt, T., Sager, H., Courties, G. et al. Chronic variable stress activates hematopoietic stem cells. Nat Med 20, 754–758 (2014). https://doi.org/10.1038/nm.3589

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