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

Viktor Janzen, Randolf Forkert, Heather E. Fleming, Yoriko Saito, Michael T. Waring, David M. Dombkowski, Tao Cheng, Ronald A. DePinho, Norman E. Sharpless and David T. Scadden ()
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Viktor Janzen: Massachusetts General Hospital, Harvard Medical School
Randolf Forkert: Massachusetts General Hospital, Harvard Medical School
Heather E. Fleming: Massachusetts General Hospital, Harvard Medical School
Yoriko Saito: Massachusetts General Hospital, Harvard Medical School
Michael T. Waring: Massachusetts General Hospital, Harvard Medical School
David M. Dombkowski: Massachusetts General Hospital, Harvard Medical School
Tao Cheng: Massachusetts General Hospital, Harvard Medical School
Ronald A. DePinho: Dana-Farber Cancer Institute, Departments of Medicine and Genetics, Harvard Medical School
Norman E. Sharpless: The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine
David T. Scadden: Massachusetts General Hospital, Harvard Medical School

Nature, 2006, vol. 443, issue 7110, 421-426

Abstract: 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.

Date: 2006
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DOI: 10.1038/nature05159

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