Movatterモバイル変換

[0]ホーム
URL:

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.

Advertisement

Nature
  • Article
  • Published:

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

Naturevolume 443, pages421–426 (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

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF

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

Figure 1:p16INK4a expression is upregulated in primitive bone marrow cell populations in aged mice and limits HSC number.
Figure 2:p16INK4a deficiency results in increased proliferation and reduced frequency of apoptotic events in a transplant setting.
Figure 3:p16INK4a 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 geneHes1.

Similar content being viewed by others

References

  1. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1.Science287, 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.Oncogene15, 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.Transplantation22, 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.Blood106, 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.Science273, 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.Cell121, 295–306 (2005)

    Article CAS  Google Scholar 

  15. Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis.Nature413, 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.Blood107, 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.Science297, 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. USA94, 1908–1913 (1997)

    Article ADS CAS  Google Scholar 

  19. Molofsky, A.V. et al. Increasingp16INK4a 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 ofBCL-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.Nature423, 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.Blood106, 827–832 (2005)

    Article CAS  Google Scholar 

  28. Kunisato, A. et al. HES-1 preserves purified hematopoietic stem cellsex vivo and accumulates side population cellsin vivo.Blood101, 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.Nature433, 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-renewalin vivo and favors lymphoid over myeloid lineage outcome.Blood99, 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.Nature439, 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

    You can also search for this author inPubMed Google Scholar

  2. Randolf Forkert

    You can also search for this author inPubMed Google Scholar

  3. Heather E. Fleming

    You can also search for this author inPubMed Google Scholar

  4. Yoriko Saito

    You can also search for this author inPubMed Google Scholar

  5. Michael T. Waring

    You can also search for this author inPubMed Google Scholar

  6. David M. Dombkowski

    You can also search for this author inPubMed Google Scholar

  7. Tao Cheng

    You can also search for this author inPubMed Google Scholar

  8. Ronald A. DePinho

    You can also search for this author inPubMed Google Scholar

  9. Norman E. Sharpless

    You can also search for this author inPubMed Google Scholar

  10. David T. Scadden

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toDavid T. Scadden.

Ethics declarations

Competing interests

Reprints and permissions information is available atwww.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

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.Nature443, 421–426 (2006). https://doi.org/10.1038/nature05159

Download citation

Access through your institution
Buy or subscribe

Editorial Summary

Stem cell ageing

In this issue, three separate labs report the discovery of a protein that regulates ageing specifically in stem cells. This helps answer a fundamental question: why do mammalian progenitor cells gradually lose their ability to divide and generate new cells as they grow old? Norman Sharpless and colleagues generated a knockout mouse lacking tumour suppressor p16INK4a, a protein involved in cell cycle control and known to be expressed in an age-dependent manner. Studying its role in regeneration of the blood, pancreas and brain, the three groups separately found that p16INK4a is not only a biomarker, but an effector of ageing. By comparing the effect of elevated or reduced p16INK4a expression in mice, they found that p16INK4a halts proliferation of stem cells, but only in older mice. Taken together, the work suggests that p16INK4a reduces cancer incidence via its tumour suppressor action, at the same time contributing to ageing by reducing stem cell function. The work also suggests that type 2 diabetes might be linked to the failure of the pancreatic islets to renew, and that blocking this protein in certain tissues might combat some effects of ageing.

Associated content

Balancing regeneration and cancer

  • Christian M Beausejour
  • Judith Campisi
NatureNews & Views

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature 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
[8]ページ先頭
©2009-2025 Movatter.jp