1. Center for Regenerative Medicine, Cancer Center, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA
2. Harvard Stem Cell Institute, Harvard University, 42 Church Street, Cambridge, Massachusetts 02138, USA
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), Boston, Massachusetts 02115, USA
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
5. *These authors contributed equally to this work
6. †Present address: Department of Radiation Oncology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA

Correspondence to: David T. Scadden^1,2 Correspondence and requests for materials should be addressed to D.T.S. (Email: scadden.david@mgh.harvard.edu).

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 p16^INK4a, 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 p16^INK4a, 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 p16^INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue.

1. Center for Regenerative Medicine, Cancer Center, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA
2. Harvard Stem Cell Institute, Harvard University, 42 Church Street, Cambridge, Massachusetts 02138, USA
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), Boston, Massachusetts 02115, USA
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
5. *These authors contributed equally to this work
6. †Present address: Department of Radiation Oncology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA

Correspondence to: David T. Scadden^1,2 Correspondence and requests for materials should be addressed to D.T.S. (Email: scadden.david@mgh.harvard.edu).

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