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Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a

Nature volume 443, pages 421–426 (2006)Cite this article

Abstract

Stem-cell ageing is thought to contribute to altered tissue maintenance and repair. Older humans experience increased bone marrow failure and poorer haematologic tolerance of cytotoxic injury. Haematopoietic stem cells (HSCs) in older mice have decreased per-cell repopulating activity, self-renewal and homing abilities, myeloid skewing of differentiation, and increased apoptosis with stress. Here we report that the cyclin-dependent kinase inhibitor p16INK4a, the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions. Notably, in the absence of p16INK4a, HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem-cell-autonomous tissue regeneration model. Inhibition of p16INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue.

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Figure 1: p16 INK4a expression is upregulated in primitive bone marrow cell populations in aged mice and limits HSC number.
Figure 2: p16 INK4a deficiency results in increased proliferation and reduced frequency of apoptotic events in a transplant setting.
Figure 3: p16 INK4a has an age-dependent effect on stem-cell repopulating ability under the stress of serial bone marrow transplantation.
Figure 4: p16INK4a regulates expression of the self-renewal-associated gene Hes1.

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Acknowledgements

We thank K. Munger for the HPV16 E7 clones. We also thank the National Institutes of Health (D.T.S., H.E.F., Y.S., T.C., R.A.D. and N.E.S.), Dr. Mildred Scheel Stiftung fuer Krebsforschung (V.J.), Deutsche Forschungsgemeinschaft (R.F.), The Ellison Medical Foundation and American Cancer Society (R.A.D.), The Paul Beeson Program in Aging Research (N.E.S.), The Sidney Kimmel Foundation (N.E.S.) and The Burroughs Wellcome Foundation (D.T.S.).

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Author notes

  1. Viktor Janzen & Randolf Forkert

    Present address: Department of Radiation Oncology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, 15213, USA

  2. Tao Cheng: *These authors contributed equally to this work

Authors and Affiliations

  1. Center for Regenerative Medicine, Cancer Center, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Massachusetts, 02114, Boston, USA

    Viktor Janzen, Randolf Forkert, Heather E. Fleming, Yoriko Saito, Michael T. Waring, David M. Dombkowski, Tao Cheng & David T. Scadden

  2. Harvard Stem Cell Institute, Harvard University, 42 Church Street, Massachusetts, 02138, Cambridge, USA

    Viktor Janzen, Randolf Forkert, Heather E. Fleming, Yoriko Saito & David T. Scadden

  3. Center for Applied Cancer Science and Department of Medical Oncology, Dana-Farber Cancer Institute, Departments of Medicine and Genetics, Harvard Medical School, 44 Binney Street (M413), Massachusetts, 02115, Boston, USA

    Ronald A. DePinho

  4. Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7295, USA

    Norman E. Sharpless

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  1. Viktor Janzen
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Correspondence to David T. Scadden.

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Janzen, V., Forkert, R., Fleming, H. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006). https://doi.org/10.1038/nature05159

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