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Rejuvenation of aged progenitor cells by exposure to a young systemic environment

Abstract

The decline of tissue regenerative potential is a hallmark of ageing and may be due to age-related changes in tissue-specific stem cells1,2,3,4,5. A decline in skeletal muscle stem cell (satellite cell) activity due to a loss of Notch signalling results in impaired regeneration of aged muscle1,6. The decline in hepatic progenitor cell proliferation owing to the formation of a complex involving cEBP-α and the chromatin remodelling factor brahma (Brm) inhibits the regenerative capacity of aged liver7. To examine the influence of systemic factors on aged progenitor cells from these tissues, we established parabiotic pairings (that is, a shared circulatory system) between young and old mice (heterochronic parabioses), exposing old mice to factors present in young serum. Notably, heterochronic parabiosis restored the activation of Notch signalling as well as the proliferation and regenerative capacity of aged satellite cells. The exposure of satellite cells from old mice to young serum enhanced the expression of the Notch ligand (Delta), increased Notch activation, and enhanced proliferation in vitro. Furthermore, heterochronic parabiosis increased aged hepatocyte proliferation and restored the cEBP-α complex to levels seen in young animals. These results suggest that the age-related decline of progenitor cell activity can be modulated by systemic factors that change with age.

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Figure 1: Heterochronic parabiosis restores muscle regeneration and muscle stem cell activation in aged animals.
Figure 2: Young serum rejuvenates activation of aged satellite cells.
Figure 3: Heterochronic parabiosis enhances proliferation of aged liver progenitor cells and restores molecular determinants of young liver regeneration.

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References

  1. Conboy, I. M., Conboy, M. J., Smythe, G. M. & Rando, T. A. Notch-mediated restoration of regenerative potential to aged muscle. Science 302, 1575–1577 (2003)

    Article  ADS  CAS  Google Scholar 

  2. Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A. & Weissman, I. L. The aging of hematopoietic stem cells. Nature Med. 2, 1011–1016 (1996)

    Article  CAS  Google Scholar 

  3. Fuller, J. Hematopoietic stem cells and aging. Sci. Aging Knowledge Environ., e11 (2002)

  4. Sigal, S. H., Brill, S., Fiorino, A. S. & Reid, L. M. The liver as a stem cell and lineage system. Am. J. Physiol. 263, G139–G148 (1992)

    CAS  PubMed  Google Scholar 

  5. Kuhn, H. G., Dickinson-Anson, H. & Gage, F. H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996)

    Article  CAS  Google Scholar 

  6. Conboy, I. M. & Rando, T. A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002)

    Article  CAS  Google Scholar 

  7. Iakova, P., Awad, S. S. & Timchenko, N. A. Aging reduces proliferative capacities of liver by switching pathways of C/EBPα growth arrest. Cell 113, 495–506 (2003)

    Article  CAS  Google Scholar 

  8. Golden, T. R., Hinerfeld, D. A. & Melov, S. Oxidative stress and aging: beyond correlation. Aging Cell 1, 117–123 (2002)

    Article  CAS  Google Scholar 

  9. Hekimi, S. & Guarente, L. Genetics and the specificity of the aging process. Science 299, 1351–1354 (2003)

    Article  CAS  Google Scholar 

  10. Tatar, M., Bartke, A. & Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 299, 1346–1351 (2003)

    Article  CAS  Google Scholar 

  11. Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003)

    Article  CAS  Google Scholar 

  12. Carlson, B. M. & Faulkner, J. A. Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol. 256, C1262–C1266 (1989)

    Article  CAS  Google Scholar 

  13. Carlson, B. M., Dedkov, E. I., Borisov, A. B. & Faulkner, J. A. Skeletal muscle regeneration in very old rats. J. Gerontol. A 56, B224–B233 (2001)

    Article  CAS  Google Scholar 

  14. McCay, C. M., Pope, F., Lunsford, W., Sperling, G. & Sambhavaphol, P. Parabiosis between old and young rats. Gerontologia 1, 7–17 (1957)

    Article  CAS  Google Scholar 

  15. Finerty, J. Parabiosis in physiological studies. Physiol. Rev. 32, 277–302 (1952)

    Article  CAS  Google Scholar 

  16. Tauchi, H. & Hasegawa, K. Change of the hepatic cells in parabiosis between old and young rats. Mech. Ageing Dev. 6, 333–339 (1977)

    Article  CAS  Google Scholar 

  17. Sidorenko, A. V., Gubrii, I. B., Andrianova, L. F., Macsijuk, T. V. & Butenko, G. M. Functional rearrangement of lymphohemopoietic system in heterochronically parabiosed mice. Mech. Ageing Dev. 36, 41–56 (1986)

    Article  CAS  Google Scholar 

  18. Wagers, A. J., Sherwood, R. I., Christensen, J. L. & Weissman, I. L. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002)

    Article  ADS  CAS  Google Scholar 

  19. 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 

  20. Partridge, T. A. Cells that participate in regeneration of skeletal muscle. Gene Ther. 9, 752–753 (2002)

    Article  CAS  Google Scholar 

  21. Sherwood, R. I., Christensen, J. L., Weissman, I. L. & Wagers, A. J. Determinants of skeletal muscle contributions from circulating cells, bone marrow cells, and hematopoietic stem cells. Stem Cells 22, 1292–1304 (2004)

    Article  Google Scholar 

  22. Rosenblatt, J. D., Lunt, A. I., Parry, D. J. & Partridge, T. A. Culturing satellite cells from living single muscle fiber explants. In Vitro Cell. Dev. Biol. Anim. 31, 773–779 (1995)

    Article  CAS  Google Scholar 

  23. Sell, S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 33, 738–750 (2001)

    Article  CAS  Google Scholar 

  24. Timchenko, N. A. et al. Regenerating livers of old rats contain high levels of C/EBPα that correlate with altered expression of cell cycle associated proteins. Nucleic Acids Res. 26, 3293–3299 (1998)

    Article  CAS  Google Scholar 

  25. Wright, D. E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001)

    Article  CAS  Google Scholar 

  26. Beauchamp, J. R. et al. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J. Cell Biol. 151, 1221–1234 (2000)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank L. Chan and K. Robinson for technical help, and T. Wyss-Coray, T. Palmer, B. Omary and M. Buckwalter for discussions. The work was supported by grants from the Burroughs Wellcome Fund Career Award to A.J.W., and from the NIH, the American Federation for Aging Research (Paul Beeson Faculty Scholar in Aging) and the Department of Veterans Affairs (Merit Review) to T.A.R.

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Correspondence to Thomas A. Rando.

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Competing interests

I.L.W. was a member of the SAB and owns significant stock in Amgen, Inc., and is a Director and owns founders stock in Stem Cells, Inc. and Cellerant, Inc.

Supplementary information

Supplementary Figure 1

Blood chimerism between parabiosed partners. (PPT 25 kb)

Supplementary Figure 2

Heterochronic parabiosis restores fiber regeneration in old mice. (PPT 100 kb)

Supplementary Figure 3

The enhancement of aged satellite cell proliferation by young serum is dependent on Notch signaling. (PPT 18 kb)

Supplementary Figure 4

Muscle regeneration in parabionts is mediated by endogenous, resident muscle stem cells, not by circulating progenitor cells. (PPT 2650 kb)

Supplementary Figure 5

Proliferating cells in livers of non-parabiotic and parabiotic mice. (PPT 1353 kb)

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Conboy, I., Conboy, M., Wagers, A. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005). https://doi.org/10.1038/nature03260

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  • DOI: https://doi.org/10.1038/nature03260

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