Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000)

    Article  ADS  CAS  Google Scholar 

  2. Walkley, C. R., Fero, M. L., Chien, W. M., Purton, L. E. & McArthur, G. A. Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells. Nature Cell Biol. 7, 172–178 (2005)

    Article  CAS  Google Scholar 

  3. Yuan, Y., Shen, H., Franklin, D. S., Scadden, D. T. & Cheng, T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nature Cell Biol. 6, 436–442 (2004)

    Article  CAS  Google Scholar 

  4. Sharpless, N. E. Ink4a/Arf links senescence and aging. Exp. Gerontol. 39, 1751–1759 (2004)

    Article  CAS  Google Scholar 

  5. Rocco, J. W. & Sidransky, D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp. Cell Res. 264, 42–55 (2001)

    Article  CAS  Google Scholar 

  6. Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004)

    Article  CAS  Google Scholar 

  7. Zindy, F., Quelle, D. E., Roussel, M. F. & Sherr, C. J. Expression of the p16INK4a tumour suppressor versus other INK4 family members during mouse development and aging. Oncogene 15, 203–211 (1997)

    Article  CAS  Google Scholar 

  8. Campisi, J. Cellular senescence as a tumour-suppressor mechanism. Trends Cell Biol. 11, S27–S31 (2001)

    Article  CAS  Google Scholar 

  9. Chen, J., Astle, C. M. & Harrison, D. E. Development and aging of primitive hematopoietic stem cells in BALB/cBy mice. Exp. Hematol. 27, 928–935 (1999)

    Article  CAS  Google Scholar 

  10. Ogden, D. A. & Mickliem, H. S. The fate of serially transplanted bone marrow cell populations from young and old donors. Transplantation 22, 287–293 (1976)

    Article  CAS  Google Scholar 

  11. 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 

  12. Liang, Y., Van Zant, G. & Szilvassy, S. J. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106, 1479–1487 (2005)

    Article  CAS  Google Scholar 

  13. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996)

    Article  ADS  CAS  Google Scholar 

  14. Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential. A revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005)

    Article  CAS  Google Scholar 

  15. Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001)

    Article  ADS  CAS  Google Scholar 

  16. Yilmaz, O. H., Kiel, M. J. & Morrison, S. J. SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. Blood 107, 924–930 (2006)

    Article  CAS  Google Scholar 

  17. 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 

  18. Morrison, S. J., Wright, D. E. & Weissman, I. L. Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl Acad. Sci. USA 94, 1908–1913 (1997)

    Article  ADS  CAS  Google Scholar 

  19. Molofsky, A.V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature advance online publication, doi:10.1038/nature05091 (6 September 2006).

  20. Siminovitch, L., Till, J. E. & McCulloch, E. A. Decline in colony-forming ability of marrow cells subjected to serial transplantation into irradiated mice. J. Cell. Physiol. 64, 23–31 (1964)

    Article  CAS  Google Scholar 

  21. Harrison, D. E. Normal function of transplanted mouse erythrocyte precursors for 21 months beyond donor life spans. Nature New Biol. 237, 220–222 (1972)

    Article  CAS  Google Scholar 

  22. Chen, J., Astle, C. M. & Harrison, D. E. Genetic regulation of primitive hematopoietic stem cell senescence. Exp. Hematol. 28, 442–450 (2000)

    Article  CAS  Google Scholar 

  23. Domen, J., Cheshier, S. H. & Weissman, I. L. The role of apoptosis in the regulation of hematopoietic stem cells: overexpression of BCL-2 increases both their number and repopulation potential. J. Exp. Med. 191, 253–264 (2000)

    Article  CAS  Google Scholar 

  24. Chkhotua, A. B. et al. Increased expression of p16(INK4a) and p27(Kip1) cyclin-dependent kinase inhibitor genes in aging human kidney and chronic allograft nephropathy. Am. J. Kidney Dis. 41, 1303–1313 (2003)

    Article  CAS  Google Scholar 

  25. Chimenti, C. et al. Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ. Res. 93, 604–613 (2003)

    Article  CAS  Google Scholar 

  26. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003)

    Article  ADS  CAS  Google Scholar 

  27. Stepanova, L. & Sorrentino, B. P. A limited role for p16Ink4a and p19Arf in the loss of hematopoietic stem cells during proliferative stress. Blood 106, 827–832 (2005)

    Article  CAS  Google Scholar 

  28. Kunisato, A. et al. HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Blood 101, 1777–1783 (2003)

    Article  CAS  Google Scholar 

  29. Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature advance online publication, doi:10.1038/nature05092 (6 September 2006).

  30. Phelps, W. C., Munger, K., Yee, C. L., Barnes, J. A. & Howley, P. M. Structure–function analysis of the human papilloma virus type 16 E7 oncoprotein. J. Virol. 66, 2418–2427 (1992)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005)

    Article  ADS  CAS  Google Scholar 

  32. Stier, S., Cheng, T., Dombkowski, D., Carlesso, N. & Scadden, D. T. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99, 2369–2378 (2002)

    Article  CAS  Google Scholar 

  33. Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2006)

    Article  ADS  CAS  Google Scholar 

Download references

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.).

Author information

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

Authors
  1. Viktor Janzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Randolf Forkert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather E. Fleming
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoriko Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael T. Waring
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David M. Dombkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tao Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ronald A. DePinho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Norman E. Sharpless
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David T. Scadden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David T. Scadden.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1–8. (PPT 1056 kb)

Supplementary Figures

This file contains text to accompany the above Supplementary Figures. (DOC 29 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05159

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing