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Hematopoietic stem cell ageing is uncoupled from p16INK4A-mediated senescence

Oncogene volume 28, pages 2238–2243 (2009)Cite this article

Abstract

Somatic stem cells are ultimately responsible for mediating appropriate organ homeostasis and have therefore been proposed to represent a cellular origin of the ageing process—a state often characterized by inappropriate homeostasis. Specifically, it has been suggested that ageing stem cells might succumb to replicative senescence by a mechanism involving the cyclin-dependent kinase inhibitor p16INK4A. Here, we tested multiple functional and molecular parameters indicative of p16INK4A activity in primary aged murine hematopoietic stem cells (HSCs). We found no evidence that replicative senescence accompanies stem cell ageing in vivo, and in line with p16INK4A being a critical determinant of such processes, most aged HSCs (>99%) failed to express p16INK4A at the mRNA level. Moreover, whereas loss of epigenetically guided repression of the INK4A/ARF locus accompanied replicative senescent murine embryonic fibroblasts, such repression was maintained in aged stem cells. Taken together, these studies indicate that increased senescence as mediated by the p16INK4A tumor suppressor has only a minor function as an intrinsic regulator of steady-state HSC ageing in vivo.

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Acknowledgements

We thank William Agace for critical review of the paper. The expert technical support from Gerd Sten is greatly appreciated. These studies were generously supported by grants to DB from the Swedish Medical Research Council, the Swedish Strategic Research Foundation, The Swedish Cancer Society, The Crafoord foundation and the Medical Faculty at Lund University.

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  1. Immunology Unit, Institution for Experimental Medical Research, Lund University, Lund, Sweden

    J L Attema, C J H Pronk, G L Norddahl, J M Nygren & D Bryder

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  1. J L Attema
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  2. C J H Pronk
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  3. G L Norddahl
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  4. J M Nygren
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  5. D Bryder
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Correspondence to D Bryder.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Attema, J., Pronk, C., Norddahl, G. et al. Hematopoietic stem cell ageing is uncoupled from p16INK4A-mediated senescence. Oncogene 28, 2238–2243 (2009). https://doi.org/10.1038/onc.2009.94

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