Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a.
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.
Janzen
Viktor
V
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Forkert
Randolf
R
Fleming
Heather E
HE
Saito
Yoriko
Y
Waring
Michael T
MT
Dombkowski
David M
DM
Cheng
Tao
T
DePinho
Ronald A
RA
Sharpless
Norman E
NE
Scadden
David T
DT
D000375:Aging; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002452:Cell Count; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; C417743:Cdkn2a protein, mouse; C489734:Hes1 protein, mouse