Letter | Published:

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

Nature volume 433, pages 760764 (17 February 2005) | Download Citation

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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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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.

Author information

Author notes

    • Irina M. Conboy
    •  & Michael J. Conboy

    These authors contributed equally to this work

    • Irina M. Conboy
    •  & Amy J. Wagers

    Present addresses: Department of Bioengineering, University of California-Berkeley, Berkeley, California 94720, USA (I.M.C.); Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA (A.J.W.)

Affiliations

  1. Department of Neurology and Neurological Sciences and

    • Irina M. Conboy
    • , Michael J. Conboy
    • , Eric R. Girma
    •  & Thomas A. Rando
  2. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Amy J. Wagers
    •  & Irving L. Weissman
  3. GRECC and Neurology Service, VA Palo Alto Health Care System, Palo Alto, California 94304, USA

    • 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.

Corresponding author

Correspondence to Thomas A. Rando.

Supplementary information

Powerpoint files

  1. 1.

    Supplementary Figure 1

    Blood chimerism between parabiosed partners.

  2. 2.

    Supplementary Figure 2

    Heterochronic parabiosis restores fiber regeneration in old mice.

  3. 3.

    Supplementary Figure 3

    The enhancement of aged satellite cell proliferation by young serum is dependent on Notch signaling.

  4. 4.

    Supplementary Figure 4

    Muscle regeneration in parabionts is mediated by endogenous, resident muscle stem cells, not by circulating progenitor cells.

  5. 5.

    Supplementary Figure 5

    Proliferating cells in livers of non-parabiotic and parabiotic mice.

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DOI

https://doi.org/10.1038/nature03260

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