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

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.

References

  1. 1

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

    ADS  CAS  Article  Google Scholar 

  2. 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)

    CAS  Article  Google Scholar 

  3. 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)

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 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)

    CAS  Article  Google Scholar 

  8. 8

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

    CAS  Article  Google Scholar 

  9. 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)

    CAS  Article  Google Scholar 

  10. 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)

    CAS  Article  Google Scholar 

  11. 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)

    CAS  Article  Google Scholar 

  12. 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)

    CAS  Article  Google Scholar 

  13. 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)

    ADS  CAS  Article  Google Scholar 

  14. 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)

    CAS  Article  Google Scholar 

  15. 15

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

    ADS  CAS  Article  Google Scholar 

  16. 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)

    CAS  Article  Google Scholar 

  17. 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)

    ADS  CAS  Article  Google Scholar 

  18. 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)

    ADS  CAS  Article  Google Scholar 

  19. 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. 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)

    CAS  Article  Google Scholar 

  21. 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)

    CAS  Article  Google Scholar 

  22. 22

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

    CAS  Article  Google Scholar 

  23. 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)

    CAS  Article  Google Scholar 

  24. 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)

    CAS  Article  Google Scholar 

  25. 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)

    CAS  Article  Google Scholar 

  26. 26

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

    ADS  CAS  Article  Google Scholar 

  27. 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)

    CAS  Article  Google Scholar 

  28. 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)

    CAS  Article  Google Scholar 

  29. 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. 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. 31

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

    ADS  CAS  Article  Google Scholar 

  32. 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)

    CAS  Article  Google Scholar 

  33. 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)

    ADS  CAS  Article  Google Scholar 

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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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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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