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Systemic signals regulate ageing and rejuvenation of blood stem cell niches

A Retraction to this article was published on 13 October 2010


Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.

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Figure 1: Exposure to young circulating factors restores LT-HSC numbers and function, and osteoblastic niche cell number in aged mice.
Figure 2: Circulating factors rejuvenate HSC regulatory activity of osteoblastic niche cells.
Figure 3: Heterochronic serum alters osteoblastic niche cell activity.
Figure 4: Neutralization of IGF-1 in vitro inhibits accumulation of HSPCs induced by aged osteoblastic niche cells.
Figure 5: Local neutralization of IGF-1 in the bone marrow inhibits accumulation of HSPCs induced by aged osteoblastic niche cells.


  1. Caspari, R. & Lee, S. H. Older age becomes common late in human evolution. Proc. Natl Acad. Sci. USA 101, 10895–10900 (2004)

    Article  ADS  CAS  Google Scholar 

  2. Rossi, D. J., Jamieson, C. H. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008)

    Article  CAS  Google Scholar 

  3. Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl Acad. Sci. USA 102, 9194–9199 (2005)

    Article  ADS  CAS  Google Scholar 

  4. Morrison, S. J. et al. The aging of hematopoietic stem cells. Nature Med. 2, 1011–1016 (1996)

    Article  CAS  Google Scholar 

  5. Liang, Y., Van Zant, G. & Szilvassy, S. J. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106, 1479–1487 (2005)

    Article  CAS  Google Scholar 

  6. Rossi, D. J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a . Nature 443, 421–426 (2006)

    Article  ADS  CAS  Google Scholar 

  8. Tothova, Z. et al. Foxos are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007)

    Article  CAS  Google Scholar 

  9. Mayack, S. R. & Wagers, A. J. Osteolineage niche cells initiate hematopoietic stem cell mobilization. Blood 112, 519–531 (2008)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  12. Jones, D. L. & Wagers, A. J. No place like home: anatomy and function of the stem cell niche. Nature Rev. Mol. Cell Biol. 9, 11–21 (2008)

    Article  CAS  Google Scholar 

  13. Wagers, A. J. & Conboy, I. M. Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell 122, 659–667 (2005)

    Article  CAS  Google Scholar 

  14. Wagers, A. J. et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002)

    Article  ADS  CAS  Google Scholar 

  15. Sherwood, R. I. et al. Isolation of adult mouse myogenic progenitors: functional heterogeneity of cells within and engrafting skeletal muscle. Cell 119, 543–554 (2004)

    Article  CAS  Google Scholar 

  16. Eggan, K. et al. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 441, 1109–1114 (2006)

    Article  ADS  CAS  Google Scholar 

  17. Balsam, L. B. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668–673 (2004)

    Article  ADS  CAS  Google Scholar 

  18. Wright, D. E. et al. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001)

    Article  ADS  CAS  Google Scholar 

  19. Osawa, M. et al. Long-term lymphohematopoietic reconstitution by a single cd34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996)

    Article  ADS  CAS  Google Scholar 

  20. Ema, H. et al. Adult mouse hematopoietic stem cells: purification and single-cell assays. Nature Protocols 1, 2979–2987 (2007)

    Article  Google Scholar 

  21. Wilson, A. & Trumpp, A. Bone-marrow haematopoietic-stem-cell niches. Nature Rev. Immunol. 6, 93–106 (2006)

    Article  CAS  Google Scholar 

  22. Arai, F., Hirao, A. & Suda, T. Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc. Med. 15, 75–79 (2005)

    Article  CAS  Google Scholar 

  23. Morrison, S. J. et al. Identification of a lineage of multipotent hematopoietic progenitors. Development 124, 1929–1939 (1997)

    CAS  PubMed  Google Scholar 

  24. Musarò, A. et al. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nature Genet. 27, 195–200 (2001)

    Article  Google Scholar 

  25. Fisher, M. C. et al. Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth. Bone 37, 741–750 (2005)

    Article  CAS  Google Scholar 

  26. Wang, Y. et al. IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone. J. Bone Miner. Res. 22, 1329–1337 (2007)

    Article  CAS  Google Scholar 

  27. Welniak, L. A. et al. Effects of organ-specific loss of insulin-like growth factor-I production on murine hematopoiesis. Biol. Blood Marrow Transplant. 10, 32–39 (2004)

    Article  CAS  Google Scholar 

  28. Gibson, L. F., Piktel, D. & Landreth, K. S. Insulin-like growth factor-1 potentiates expansion of interleukin-7-dependent pro-b cells. Blood 82, 3005–3011 (1993)

    Article  CAS  Google Scholar 

  29. Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007)

    Article  ADS  CAS  Google Scholar 

  30. Liu, H. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803–806 (2007)

    Article  ADS  CAS  Google Scholar 

  31. Kuro-o & M Klotho as a regulator of oxidative stress and senescence. Biol. Chem. 389, 233–241 (2008)

    Article  CAS  Google Scholar 

  32. Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000)

    Article  ADS  CAS  Google Scholar 

  33. 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  Google Scholar 

  34. DiGirolamo, D. J. et al. Mode of growth hormone action in osteoblasts. J. Biol. Chem. 282, 31666–31674 (2007)

    Article  CAS  Google Scholar 

  35. Fulzele, K. et al. Disruption of the insulin-like growth factor type 1 receptor in osteoblasts enhances insulin signaling and action. J. Biol. Chem. 282, 25649–25658 (2007)

    Article  CAS  Google Scholar 

  36. Nakasaki, M. et al. IGF-I secreted by osteoblasts acts as a potent chemotactic factor for osteoblasts. Bone 43, 869–879 (2008)

    Article  CAS  Google Scholar 

  37. Cornish, J. et al. Shared pathways of osteoblast mitogenesis induced by amylin, adrenomedullin, and IGF-1. Biochem. Biophys. Res. Commun. 318, 240–246 (2004)

    Article  CAS  Google Scholar 

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This work was supported in part by funding from the Burroughs-Welcome Fund, WM Keck Foundation, Glenn Foundation, and National Institutes of Health (NIH) 1 DP2 OD004345-01 (to A.J.W.), by fellowships from the NIH (T32DK07260-29) and the Iacocca Foundation (to S.R.M.), and by the Joslin Diabetes Center DERC (P30DK036836). We thank J. LaVecchio and G. Buruzula for expert cell sorting, C. J. Luckey for anti-IGF-1 antibody, and L. Zon, R. Lee, D. Rossi, L. P. Kane, S. Lowe and C. Dall’Osso for helpful advice and critical reading of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author Contributions S.R.M. and A.J.W. designed and interpreted experiments. S.R.M. performed and analysed the experiments. J.L.S. assisted in parabiosis procedures, and F.S.K. assisted in LT-HSC analysis from parabiotic mice.

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Correspondence to Amy J. Wagers.

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Mayack, S., Shadrach, J., Kim, F. et al. Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature 463, 495–500 (2010).

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