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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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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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