Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16 INK4a

Viktor Janzen; Randolf Forkert; Heather E. Fleming; Yoriko Saito; Michael T. Waring; David M. Dombkowski; Tao Cheng; Ronald A. DePinho; Norman E. Sharpless; David T. Scadden

doi:10.1038/nature05159

Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16 ^INK4a

Viktor Janzen, Randolf Forkert, Heather E. Fleming, Yoriko Saito, Michael T. Waring, David M. Dombkowski, Tao Cheng, Ronald A. DePinho, Norman E. Sharpless, David T. Scadden

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936 Scopus citations

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.

Original language	English (US)
Pages (from-to)	421-426
Number of pages	6
Journal	Nature
Volume	443
Issue number	7110
DOIs	https://doi.org/10.1038/nature05159
State	Published - Sep 28 2006
Externally published	Yes

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@article{e4d29232912b441f88bfc5864eb4dec3,

title = "Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16 INK4a",

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 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.",

author = "Viktor Janzen and Randolf Forkert and Fleming, {Heather E.} and Yoriko Saito and Waring, {Michael T.} and Dombkowski, {David M.} and Tao Cheng and DePinho, {Ronald A.} and Sharpless, {Norman E.} and Scadden, {David T.}",

note = "Funding Information: 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.).",

year = "2006",

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doi = "10.1038/nature05159",

language = "English (US)",

volume = "443",

pages = "421--426",

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AU - Janzen, Viktor

AU - Forkert, Randolf

AU - Fleming, Heather E.

AU - Saito, Yoriko

AU - Waring, Michael T.

AU - Dombkowski, David M.

AU - Cheng, Tao

AU - DePinho, Ronald A.

AU - Sharpless, Norman E.

AU - Scadden, David T.

N1 - Funding Information: 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.).

PY - 2006/9/28

Y1 - 2006/9/28

N2 - 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 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.

AB - 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 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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Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16 ^INK4a

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