The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
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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In the citing paper
“This correlates with the accumulation of DNA damage (Rossi et al., 2007), and with the overexpression of cell cycle-inhibitory proteins such as p16INK4a”
From The Hallmarks of Aging (2013) · cites this paper as Janzen et al., 2006
In the citing paper
“old INK4a−/− HSCs exhibit better engraftment capacity and increased cell cycle activity compared with old wild-type HSCs”
From The Hallmarks of Aging (2013) · cites this paper as Janzen et al., 2006
In the citing paper
“Old p16INK4a−/− HSCs also exhibit increased cell cycle activity and enhanced engraftment128, although these enhancements come with a price, as p16INK4a−/− animals show an increased incidence of malignancy.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [128]
In the citing paper
“Old p16INK4a−/− HSCs also exhibit increased cell cycle activity and enhanced engraftment128, although these enhancements come with a price, as p16INK4a−/− animals show an increased incidence of malignancy.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [128]
In the citing paper
“but knockout of p16 increases the life-span of HSCs by promoting HSC self-renewal.16-19”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [19]
In the citing paper
“ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.15,19,20,35-38”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [19]
In the citing paper
“age-induced expression of p16INK4a in adult stem cells seems to be associated with widespread impairment in tissue regeneration 23, 24, 25”
From The common biology of cancer and ageing (2007) · cites this paper as [23]
Citations
Cites
Rejuvenation of aged progenitor cells by exposure to a young systemic environment
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Long-Term Lymphohematopoietic Reconstitution by a Single CD34-Low/Negative Hematopoietic Stem Cell
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Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
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Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
Self-citationLittle Evidence for Developmental Plasticity of Adult Hematopoietic Stem Cells
Wagers, A. J., Sherwood, R. I., Christensen, J. L., & Weissman, I. L. (2002) · Science · doi:10.1126/science.1074807 · Cited by 1,460
Hematopoietic Stem Cell Quiescence Maintained by p21 cip1/waf1
Cheng, T., Rodrigues, N., Shen, H., Yang, Y.-G., Dombkowski, D., Sykes, M., & Scadden, D. T. (2000) · Science · doi:10.1126/science.287.5459.1804 · Cited by 1,339
Self-citationIdentification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential
Adolfsson, J., Månsson, R., Buza-Vidas, N., Hultquist, A., Liuba, K., Jensen, C. T., Bryder, D., Yang, L., Borge, O. J., Thorén, L., et al. (2005) · Cell · doi:10.1016/j.cell.2005.02.013 · Cited by 1,323
p16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003
Self-citationIncreasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature05091 · Cited by 972
Self-citationThe aging of hematopoietic stem cells
Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A., & Weissman, I. L. (1996) · Nature Medicine · doi:10.1038/nm0996-1011 · Cited by 853
Cited by
Sorted by citations
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
ROS function in redox signaling and oxidative stress
Schieber, M., & Chandel, N. S. (2014) · Current Biology · doi:10.1016/j.cub.2014.03.034 · Cited by 6,931
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Jones, P. A., & Baylin, S. B. (2007) · Cell · doi:10.1016/j.cell.2007.01.029 · Cited by 4,515
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
Metadata
- Authors
- Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T.
- Affiliations
- Harvard University (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Scadden, David T.
- ORCID
- Venue
- Nature
- Published
- 2006-09
- Volume
- 443
- Issue
- 7110
- Pages
- 421-426
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2084289371
- Cited by
- 1,106
- References
- 33
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 17 · 2023: 21 · 2022: 48 · 2021: 34 · 2020: 37 · 2019: 44 · 2018: 39 · 2017: 57 · 2016: 57 · 2015: 62 · 2014: 66 · 2013: 70 · 2012: 59
- FWCI
- 63.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p16INK4a, stem cell aging, hematopoietic stem cells, cyclin-dependent kinase inhibitors, tumour suppressor, stem cell self-renewal, apoptosis, stress tolerance, tissue regeneration, pancreatic islet regeneration, brain regeneration, type 2 diabetes, bone marrow failure
- MeSH terms
- Transcription Factor HES-1, Aging, Animals, Cell Count, Hematopoietic Stem Cells, Bone Marrow Transplantation, Cellular Senescence, Apoptosis, Homeodomain Proteins, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins
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