Total body irradiation selectively induces murine hematopoietic stem cell senescence.
Open accessAbstract
Exposure to ionizing radiation (IR) and certain chemotherapeutic agents not only causes acute bone marrow (BM) suppression but also leads to long-term residual hematopoietic injury. This latter effect has been attributed to damage to hematopoietic stem cell (HSC) self-renewal. Using a mouse model, we investigated whether IR induces senescence in HSCs, as induction of HSC senescence can lead to the defect in HSC self-renewal. It was found that exposure of C57BL/6 mice to a sublethal dose (6.5 Gy) of total body irradiation (TBI) resulted in a sustained quantitative and qualitative reduction of LKS+ HSCs. In addition, LKS+ HSCs from irradiated mice exhibited an increased expression of the 2 commonly used biomarkers of cellular senescence, p16(Ink4a) and SA-beta-gal. In contrast, no such changes were observed in irradiated LKS- hematopoietic progenitor cells. These results provide the first direct evidence demonstrating that IR exposure can selectively induce HSC senescence. Of interest, the induction of HSC senescence was associated with a prolonged elevation of p21(Cip1/Waf1), p19(Arf), and p16(Ink4a) mRNA expression, while the expression of p27(Kip1) and p18(Ink4c) mRNA was not increased following TBI. This suggests that p21(Cip1/Waf1), p19(Arf), and p16(Ink4a) may play an important role in IR-induced senescence in HSCs.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Increased expression of p16 and Arf has been implicated in mediating induction of senescence in a variety of cells including HSCs and is the most robust biomarker of senescence cells besides SA-β-gal staining.
“Increased expression of p16 and Arf has been implicated in mediating induction of senescence in a variety of cells including HSCs and is the most robust biomarker of senescence cells besides SA-β-gal staining.8,24,25”
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 [8]
Upregulation of p16 and Arf has been implicated in mediating induction of HSC senescence in a variety of pathological conditions and during aging.
“upregulation of p16 and Arf has been implicated in mediating induction of HSC senescence in a variety of pathological conditions and during aging,8,41,42”
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 [8]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · see citing works
Long-Term Lymphohematopoietic Reconstitution by a Single CD34-Low/Negative Hematopoietic Stem Cell
Osawa, M., Hanada, K., Hamada, H., & Nakauchi, H. (1996) · Science · doi:10.1126/science.273.5272.242 · Cited by 2,141 · see citing works
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871 · see citing works
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 · see citing works
Hematopoietic Stem Cell Quiescence Maintained by p21 <sup>cip1/waf1</sup>
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 · see citing works
Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., et al. (2004) · Nature · doi:10.1038/nature02989 · Cited by 1,175 · see citing works
Association of Spindle Assembly Checkpoint Component XMAD2 with Unattached Kinetochores
Chen, R., Waters, J. C., Salmon, E. D., & Murray, A. W. (1996) · Science · doi:10.1126/science.274.5285.242 · Cited by 783 · see citing works
Tumor suppression by Ink4a-Arf: progress and puzzles.
Lowe, S. W., & Sherr, C. J. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00013-8 · Cited by 699 · see citing works
The INK4A/ARF locus and its two gene products.
Sharpless, N. E., & DePinho, R. A. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80004-5 · Cited by 533 · see citing works
Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1
Iwama, A., Oguro, H., Negishi, M., Kato, Y., Morita, Y., Tsukui, H., Ema, H., Kamijo, T., Katoh-Fukui, Y., Koseki, H., et al. (2004) · Immunity · doi:10.1016/j.immuni.2004.11.004 · Cited by 515 · see citing works
Putting the stress on senescence
Serrano, M., & Blasco, M. A. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00278-7 · Cited by 413 · see citing works
An in vitro limiting-dilution assay of long-term repopulating hematopoietic stem cells in the mouse
Ploemacher, R., van der Sluijs, J., Voerman, J., & Brons, N. (1989) · Blood · doi:10.1182/blood.v74.8.2755.2755 · Cited by 396 · see citing works
Stem cell repopulation efficiency but not pool size is governed by p27kip1
Cheng, T., Rodrigues, N. P., Dombkowski, D., Stier, S., & Scadden, D. T. (2000) · Nature Medicine · doi:10.1038/81335 · Cited by 347 · see citing works
Domen, J., Gandy, K. L., & Weissman, I. L. (1998) · Blood · doi:10.1182/blood.v91.7.2272 · Cited by 293 · see citing works
Yuan, Y., Shen, H., Franklin, D. S., Scadden, D. T., & Cheng, T. (2004) · Nature Cell Biology · doi:10.1038/ncb1126 · Cited by 269 · see citing works
Hematopoietic stem cells expand during serial transplantation in vivo without apparent exhaustion
Iscove, N. N., & Nawa, K. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00341-1 · Cited by 214 · see citing works
Asymmetric Division and Lineage Commitment at the Level of Hematopoietic Stem Cells
Takano, H., Ema, H., Sudo, K., & Nakauchi, H. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20030929 · Cited by 208 · see citing works
Meng, A., Wang, Y., Zant, G. E. V., & Zhou, D. (2003) · PubMed · Cited by 193 · see citing works
Self-citationTesta, N. G., Hendry, J. H., & Molineux, G. (1985) · PubMed · Cited by 141 · see citing works
Walkley, C. R., Fero, M. L., Chien, W., Purton, L. E., & McArthur, G. A. (2005) · Nature Cell Biology · doi:10.1038/ncb1214 · Cited by 112 · see citing works
Stem cell depletion: An explanation of the late effects of cytotoxins
Hellmän, S., & Botnick, L. E. (1977) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(77)90028-1 · Cited by 97 · see citing works
Human three-dimensional fibroblast cultures express angiogenic activity
Pinney, E., Liu, K., Sheeman, B., & Mansbridge, J. N. (2000) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(200004)183:1 · Cited by 94 · see citing works
Meng, A., Wang, Y., Brown, S. A., Zant, G. E. V., & Zhou, D. (2003) · Experimental Hematology · doi:10.1016/j.exphem.2003.08.014 · Cited by 90 · see citing works
Self-citationPhelps, D. E., Hsiao, K., Li, Y., Hu, N., Franklin, D. S., Westphal, E., Lee, E. Y.-H. P., & Xiong, Y. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.4.2334 · Cited by 86 · see citing works
Hematopoietic stem cell deficit of transplanted bone marrow previously exposed to cytotoxic agents.
Neben, S., Hellmän, S., Montgomery, M., Ferrara, J. L. M., Mauch, P., & Hemman, S. (1993) · PubMed · Cited by 86 · see citing works
Stepanova, L., & Sorrentino, B. P. (2005) · Blood · doi:10.1182/blood-2004-06-2242 · Cited by 68 · see citing works
Permanent loss in stem cell self renewal capacity following stress to the marrow
Mauch, P. M., Rosenblatt, M., & Hellmän, S. (1988) · Blood · doi:10.1182/blood.v72.4.1193.1193 · Cited by 68 · see citing works
van Os, R., Robinson, S., Sheridan, T., & Mauch, P. M. (2000) · Stem Cells · doi:10.1634/stemcells.18-2-120 · Cited by 57 · see citing works
Testa, N. G., Gale, R. P., & Bulova, S. I. (1989) · American Journal of Clinical Oncology · doi:10.1097/00000421-198904000-00022 · Cited by 32 · see citing works
Managing hematologic toxicities.
Capo, G., & Waltzman, R. J. (2004) · PubMed · Cited by 9 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [20]Cheng T, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287: 1804-1808. [DOI] [PubMed] [Google Scholar]
- [30]Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol. 2000;183: 10-17. [DOI] [PubMed] [Google Scholar]
Cited by
Sorted by citations
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., et al. (2016) · Nature Medicine · doi:10.1038/nm.4010 · Cited by 1,819 · see citing works
Self-citationp16INK4a 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 · see citing works
The Regulation of INK4/ARF in Cancer and Aging
Kim, W. Y., & Sharpless, N. E. (2006) · Cell · doi:10.1016/j.cell.2006.10.003 · Cited by 1,009 · see citing works
Cellular senescence and tumor suppressor gene p16
Rayess, H., Wang, M. B., & Srivatsan, E. S. (2012) · International Journal of Cancer · doi:10.1002/ijc.27316 · Cited by 825 · see citing works
DNA repair is limiting for haematopoietic stem cells during ageing
Nijnik, A., Woodbine, L., Marchetti, C., Dawson, S., Lambe, T., Liu, C., Rodrigues, N. P., Crockford, T. L., Cabuy, E., Vindigni, A., et al. (2007) · Nature · doi:10.1038/nature05875 · Cited by 518 · see citing works
Space Radiation: The number one risk to astronaut health beyond low earth orbit
Chancellor, J., Scott, G., & Sutton, J. (2014) · Life · doi:10.3390/life4030491 · Cited by 455 · see citing works
Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation
Inomata, K., Aoto, T., Binh, N. T., Okamoto, N., Tanimura, S., Wakayama, T., Iseki, S., Hara, E., Masunaga, T., Shimizu, H., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.037 · Cited by 368 · see citing works
p53-Mediated Hematopoietic Stem and Progenitor Cell Competition
Bondar, T., & Medzhitov, R. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.03.002 · Cited by 342 · see citing works
Wang, Y., Liu, L., Pazhanisamy, S. K., Li, H., Meng, A., & Zhou, D. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.11.005 · Cited by 273 · see citing works
Self-citationCordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents
Wang, Z., Chen, Z., Jiang, Z., Luo, P., Liu, L., Huang, Y., Wang, H., Wang, Y., Long, L., Tan, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10386-8 · Cited by 219 · see citing works
Self-citationT cell regeneration after immunological injury
Velardi, E., Tsai, J. J., & van den Brink, M. R. M. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-020-00457-z · Cited by 222 · see citing works
Le, O. N. L., Rodier, F., Fontaine, F., Coppe, J., Campisi, J., DeGregori, J., Laverdière, C., Kokta, V., Haddad, E., & Beauséjour, C. M. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00567.x · Cited by 168 · see citing works
Shao, L., Feng, W., Li, H., Gardner, D., Luo, Y., Wang, Y., Liu, L., Meng, A., Sharpless, N. E., & Zhou, D. (2014) · Blood · doi:10.1182/blood-2013-07-515619 · Cited by 165 · see citing works
Self-citationIrradiation selects for p53-deficient hematopoietic progenitors.
Marusyk, A., Porter, C. C., Zaberezhnyy, V., & DeGregori, J. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000324 · Cited by 151 · see citing works
Hematopoietic stem cell exhaustion impacted by p18INK4C and p21Cip1/Waf1 in opposite manners
Yu, H., Yuan, Y., Shen, H., & Cheng, T. (2006) · Blood · doi:10.1182/blood-2005-02-0685 · Cited by 127 · see citing works
Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway
Probin, V., Wang, Y., & Zhou, D. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.03.020 · Cited by 105 · see citing works
Self-citationLi, H., Wang, Y., Pazhanisamy, S. K., Shao, L., Batinic-Haberle, I., Meng, A., & Zhou, D. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.016 · Cited by 68 · see citing works
Wang, Y., Liu, L., & Zhou, D. (2011) · Radiation Research · doi:10.1667/rr2727.1 · Cited by 67 · see citing works
Self-citationShen, H., Yu, H., Liang, P. H., Cheng, H., XuFeng, R., Yuan, Y., Zhang, P., Smith, C. A., & Cheng, T. (2012) · Blood · doi:10.1182/blood-2011-08-373621 · Cited by 62 · see citing works
Carbonneau, C. L., Despars, G., Rojas-Sutterlin, S., Fortin, A., Le, O., Hoang, T., & Beauséjour, C. M. (2012) · Blood · doi:10.1182/blood-2011-06-361626 · Cited by 59 · see citing works
Wang, Y. V., Leblanc, M., Fox, N., Mao, J.-H., Tinkum, K. L., Krummel, K., Engle, D., Piwnica-Worms, D., Piwnica-Worms, H., Balmain, A., et al. (2011) · Genes & Development · doi:10.1101/gad.2024411 · Cited by 53 · see citing works
Self-citationMishima, K., Inoue, H., Nishiyama, T., Mabuchi, Y., Amano, Y., Ide, F., Matsui, M., Yamada, H., Yamamoto, G., Tanaka, J., et al. (2012) · Stem Cells · doi:10.1002/stem.1173 · Cited by 42 · see citing works
Frescas, D., Hall, B. M., Strom, E., Virtuoso, L. P., Gupta, M., Gleiberman, A. S., Rydkina, E., Balan, V., Vujcic, S., Chernova, O. B., et al. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1339850 · Cited by 34 · see citing works
LI, D., WANG, Y., WU, H., LU, L., ZHANG, H., CHANG, J., ZHAI, Z., ZHANG, J., WANG, Y., ZHOU, D., et al. (2011) · Journal of Radiation Research · doi:10.1269/jrr.11007 · Cited by 28 · see citing works
Self-citation
- Authors
- Wang, Y., Schulte, B. A., LaRue, A. C., Ogawa, M., & Zhou, D.
- Affiliations
- United States Department of Veterans Affairs (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-01-01
- Volume
- 107
- Issue
- 1
- Pages
- 358-366
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895367
- OpenAlex
- W1992336853
- Cited by
- 351
- References
- 31
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 12 · 2023: 15 · 2022: 13 · 2021: 17 · 2020: 14 · 2019: 15 · 2018: 16 · 2017: 25 · 2016: 21 · 2015: 27 · 2014: 22 · 2013: 18 · 2012: 18
- FWCI
- 6.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01 HL69123, R01HL069123)
- National Cancer Institute (CA102558, R01CA102558, R01CA078688, R01 CA 78688, R01CA86688)
- National Institute on Deafness and Other Communication Disorders (R01DC-00713, R01DC000713)
- National Center for Research Resources (C06 RR 14516, C06RR014516)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- total body irradiation, ionizing radiation, HSC self-renewal, p16INK4a, p19ARF, p21, SA-β-galactosidase, hematopoietic progenitor cells, sublethal radiation dose
- MeSH terms
- Animals, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, RNA, Messenger, Whole-Body Irradiation, Up-Regulation, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p19, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
