Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Abstract
The 'ataxia telangiectasia mutated' (Atm) gene maintains genomic stability by activating a key cell-cycle checkpoint in response to DNA damage, telomeric instability or oxidative stress. Mutational inactivation of the gene causes an autosomal recessive disorder, ataxia-telangiectasia, characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature ageing and a high incidence of lymphoma. Here we show that ATM has an essential function in the reconstitutive capacity of haematopoietic stem cells (HSCs) but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-/- mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of Atm-/- HSCs, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a)-retinoblastoma (Rb) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-/- HSCs. These results show that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress.
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Antioxidants have potential to improve the function of old hematopoietic stem cells.
“other studies have shown the potential of antioxidants to improve the function of old HSCs (76,96).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [96]
In mouse HSCs and neural stem cells, excessive cellular ROS concentrations cause abnormal proliferation, malignancy, and compromised self-renewal.
“in HSCs and neural stem cells (NSCs) of mice, excessive cellular ROS concentrations lead to abnormal proliferation, malignancy and compromised stem cell self-renewal11–14”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
Experimentally induced genetic disruption of DDR pathways in mice produces cell-autonomous defects in HSC function.
“experimentally induced genetic disruption of DDR pathways in mice also produces cell-autonomous defects in HSC function, as assayed by in vivo hematopoietic reconstitution and in vitro colony forming assays11,36,52,53.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
Age-dependent alterations in SOD2 regulation by FoxO3 and ATM contribute to loss of HSC function with aging.
“age-dependent alterations in regulation of SOD2 by FoxO3 and the DNA damage sensing serine/threonine protein kinase ATM (ataxia-telangiectasia mutated) have been shown to contribute to loss of HSC function with aging11,16, 24.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
ATM functions in regulating intracellular ROS levels and sensitivity to these molecules.
“Another potential function for ATM in suppressing progeroid phenotypes may be related to reported ATM functions in regulating intracellular ROS levels and sensitivity to these molecules (Barzilai et al., 2002; Ito et al., 2004”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ito et al., 2004
Inactivation of the p16-Rb pathway restores the reproductive function of ATM−/− HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.
“Inactivation of the p16-Rb pathway restores the reproductive function of ATM−/− HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.20,21”
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 [20]
Mutation of the ataxia telangiectasia mutated (ATM) gene results in upregulation of p16 and Arf in HSCs.
“Furthermore, mutation of the ataxia telangiectasia mutated (ATM) gene also results in upregulation of p16 and Arf in HSCs.”
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 [20]
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.
“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 [20]
Mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment.
“mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment 34”
From The common biology of cancer and ageing (2007) · cites this paper as [34]
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“ROS levels have been demonstrated to influence stem cell self-renewal and the onset of differentiation in multiple systems (Ito et al., 2004; Owusu-Ansah and Banerjee, 2009; Smith et al., 2000; Tothova and Gilliland, 2007).”
Phan, L. M., Yeung, S. J., & Lee, M. H. (2014) · Europe PMC (PubMed Central) · doi:10.7497/j.issn.2095-3941.2014.01.001 · Cited by 500 · see citing works
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“ROS has previously been identified as causative for the HSC defects observed in mice lacking the ataxia telanegiectasia gene Atm, in which multilineage bone marrow failure due to HSC exhaustion was evident (Ito et al., 2004).”
BackgroundMitochondria as Signaling Organelles Control Mammalian Stem Cell Fate
Chakrabarty, R. P., & Chandel, N. S. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.02.011 · Cited by 490 · see citing works
“Similarly, increased ROS levels in ATM-deficient mice cause HSC exhaustion by activating the p38-MAPK pathway, which can be reversed by prolonged treatment with an antioxidant or a p38-MAPK inhibitor (Ito et al., 2004).”
BackgroundFoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis
Paik, J.-H., Ding, Z., Narurkar, R., Ramkissoon, S., Muller, F., Kamoun, W. S., Chae, S.-S., Zheng, H., Ying, H., Mahoney, J., et al. (2009) · Cell Stem Cell · doi:10.1016/j.stem.2009.09.013 · Cited by 459 · see citing works
“…cycle/quiescence, apoptosis, and intracellular redox status in the maintenance and fate determination within tissue stem cell compartment (Cheng et al., 2000a, 2000b; Doetsch et al., 2002b; Ito et al., 2004, 2006; Kippin et al., 2005; Kozar et al., 2004; Malumbres et al., 2004; Yuan et al., 2004).”
BackgroundPaull, T. T. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-034335 · Cited by 458 · see citing works
ATM activates the pentose phosphate pathway promoting anti‐oxidant defence and DNA repair
Cosentino, C., Grieco, D., & Costanzo, V. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.330 · Cited by 436 · see citing works
“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”
BackgroundMonitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model
Burd, C. E., Sorrentino, J. A., Clark, K. S., Darr, D. B., Krishnamurthy, J., Deal, A. M., Bardeesy, N., Castrillon, D. H., Beach, D. H., & Sharpless, N. E. (2013) · Cell · doi:10.1016/j.cell.2012.12.010 · Cited by 419 · see citing works
“…has largely focused on cell-intrinsic activators of p16INK4a expression such as DNA damage (Pavey et al., 1999), telomere shortening (Bartkova et al., 2006; Jacobs and de Lange, 2004), production of reactive oxygen species (Ito et al., 2004), and stalled replication forks (Ressler et al., 2006).”
SIRT3 Reverses Aging-Associated Degeneration
Brown, K., Xie, S., Qiu, X., Mohrin, M., Shin, J., Liu, Y., Zhang, D., Scadden, D. T., & Chen, D. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.005 · Cited by 436 · see citing works
“Deficient intracellular management of ROS results in increased stem cell cycling and apoptosis, as well as compromised self-renewal and differentiation, resembling essential aspects of aged stem cells (Ito et al., 2004; Ito et al., 2006; Miyamoto et al., 2007; Paik et al., 2009; Renault et al., 2009; Tothova et al., 2…”
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Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment
Walkley, C. R., Shea, J. M., Sims, N. A., Purton, L. E., & Orkin, S. H. (2007) · Cell · doi:10.1016/j.cell.2007.03.055 · Cited by 424 · see citing works
“The ‘‘Rb pathway’’ has also been implicated in phenotypes observed in both the Bmi1 / and ATM / HSCs (Ito et al., 2004; Lessard and Sauvageau, 2003; Park et al., 2003).”
Reactive Oxygen Species in Normal and Tumor Stem Cells
Zhou, D.-H., Shao, L.-J., & Spitz, D. (2014) · Advances in Cancer Research · doi:10.1016/b978-0-12-420117-0.00001-3 · Cited by 323 · see citing works
“Treatment of Atm−/− mice with N-acetylcysteine (NAC) can restore the function of HSCs and prevent the development of BM failure (Ito et al., 2004).”
BackgroundInfluentialLeukemia Stem Cells and Microenvironment: Biology and Therapeutic Targeting
Konopleva, M. Y., & Jordan, C. T. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.31.0904 · Cited by 401 · see citing works
DNA damage checkpoints in stem cells, ageing and cancer
Sperka, T., Wang, J., & Rudolph, K. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3420 · Cited by 393 · see citing works
Role of mitochondrial reactive oxygen species in homeostasis regulation
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“and the stem cell pool was depleted [78,86,87].”
BackgroundSignal Transduction by Mitochondrial Oxidants
Finkel, T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r111.271999 · Cited by 390 · see citing works
Vitale, I., Manic, G., De Maria, R., Kroemer, G., & Galluzzi, L. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.006 · Cited by 361 · see citing works
“HSCs also limit oxidative stress by activating ATM and forkhead box O (FOXO) signaling (Ito et al., 2004; Tothova et al., 2007) and autophagy (Mortensen et al., 2011). p53 rapidly controls HSCs accumulating genetic damage beyond repair (via RCD or senescence) (Wang et al., 2014).”
BackgroundOxidative Stress in the Regulation of Normal and Neoplastic Hematopoiesis
Ghaffari, S. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2142 · Cited by 377 · see citing works
“Studies by Suda and colleagues (49) showed recently that regulation of ROS by ATM is essential for hematopoietic stem cell self-renewal, because loss of ATM results in ROS-mediated depletion of the hematopoietic stem cell pool, leading to bone marrow failure in old mice.”
InfluentialGenotoxic 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
“ATM and ATR deficiency have been shown to degrade tissue renewal capacity through stem cell depletion with or without exogenous genotoxic stress (Ito et al., 2004; Ruzankina et al., 2007; Takubo et al., 2008).”
Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche
Chen, J. Y., Miyanishi, M., Wang, S. K., Yamazaki, S., Sinha, R., Kao, K. S., Seita, J., Sahoo, D., Nakauchi, H., & Weissman, I. L. (2016) · Nature · doi:10.1038/nature16943 · Cited by 345 · see citing works
Mitochondrial dysfunction in ataxia-telangiectasia
Valentin-Vega, Y. A., MacLean, K. H., Tait-Mulder, J., Milasta, S., Steeves, M., Dorsey, F. C., Cleveland, J. L., Green, D. R., & Kastan, M. B. (2012) · Blood · doi:10.1182/blood-2011-08-373639 · Cited by 365 · see citing works
“Nat Rev Mol Cell Biol 2008; 9(10):759-769.”
Redox Regulation by Keap1 and Nrf2 Controls Intestinal Stem Cell Proliferation in Drosophila
Hochmuth, C. E., Biteau, B., Bohmann, D., & Jasper, H. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.006 · Cited by 364 · see citing works
“These findings support the idea that the intracellular redox balance is a critical determinant of stem cell function in various systems (Ito et al., 2004; Liu et al., 2009; Owusu-Ansah and Banerjee, 2009; Smith et al., 2000; Tothova et al., 2007; Tsatmali et al., 2005) and suggest that this balance is dynamically regu…”
BackgroundInfluentialSignaling pathways governing stem-cell fate
Blank, U., Karlsson, G., & Karlsson, S. (2007) · Blood · doi:10.1182/blood-2007-07-075168 · Cited by 350 · see citing works
Total body irradiation selectively induces murine hematopoietic stem cell senescence.
Wang, Y., Schulte, B. A., LaRue, A. C., Ogawa, M., & Zhou, D. (2006) · Blood · doi:10.1182/blood-2005-04-1418 · Cited by 351 · see citing works
Cell state-specific metabolic dependency in hematopoiesis and leukemogenesis
Wang, Y.-H., Israelsen, W. J., Lee, D., Yu, V. W. C., Jeanson, N. T., Clish, C., Cantley, L., Heiden, M. V. V., & Scadden, D. (2014) · Cell · doi:10.1016/j.cell.2014.07.048 · Cited by 342 · see citing works
“Because excess ROS has been shown to impair HSC maintenance and long-term repopulation ability (Ito et al., 2004), the increased production of Wang et al.”
DNA-Damage Response in Tissue-Specific and Cancer Stem Cells
Blanpain, C., Mohrin, M., Sotiropoulou, P. A., & Passegue, E. A. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.012 · Cited by 350 · see citing works
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Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock
Mantel, C., O’Leary, H. A., Chitteti, B. R., Huang, X., Cooper, S. H., Hangoc, G., Brustovetsky, N., Srour, E. F., Lee, M. R., Messina‐Graham, S., et al. (2015) · Cell · doi:10.1016/j.cell.2015.04.054 · Cited by 335 · see citing works
“, 2010), a normal by-product of respiration that promotes HSC differentiation (Broxmeyer and Mantel, 2012; Ito et al., 2004; 2006; Tothova and Gilliland, 2009; Yalcin et al., 2008).”
Ludin, A., Gur‐Cohen, S., Golan, K., Kaufmann, K. B., Itkin, T., Medaglia, C., Lu, X., Ledergor, G., Kollet, Ó., & Lapidot, T. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.5941 · Cited by 333 · see citing works
Cadmium-Induced Pathologies: Where Is the Oxidative Balance Lost (or Not)?
Nair, A., DeGheselle, O., Smeets, K., Kerkhove, E. V., & Cuypers, A. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14036116 · Cited by 333 · see citing works
Effects of Oxidative Stress on Mesenchymal Stem Cell Biology
Denu, R. A., & Hematti, P. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/2989076 · Cited by 331 · see citing works
“In MSCs, excess ROS or exogenous addition of H 2 O 2 can impair selfrenewal, differentiation capacity, and proliferation [57–61]; concordantly, antioxidants stimulate MSC proliferation [62].”
BackgroundHematopoietic Stem Cell Injury Induced by Ionizing Radiation
Shao, L., Luo, Y., & Zhou, D. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5635 · Cited by 337 · see citing works
“Inactivation of the p16-Rb pathway by retroviral transfection of HPV E7 proteins restores the reproductive function of ATM - / - HSCs, whereas inhibition of the Arf-p53 pathway by E6 transfection has no such effect (67).”
FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System
Tothova, Z., & Gilliland, D. G. (2007) · Cell Stem Cell · doi:10.1016/j.stem.2007.07.017 · Cited by 331 · see citing works
Lu, T., & Finkel, T. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.01.011 · Cited by 327 · see citing works
“This oxidative stress results in a very rapid (months) decline in HSC number and function [27].”
BackgroundReactive Oxygen Species in Cancer Stem Cells
Shi, X., Zhang, Y., Zheng, J., & Pan, J. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4529 · Cited by 326 · see citing works
“Consistent with the results, ATM knockout mice displayed increased levels of ROS in many organs, and the mechanism may involve the reduced capacity of the major antioxidant enzymes, including catalase, GPX, SOD, and glutathione reductase (58), but the links between ATM and these genes are not clear.”
BackgroundThe ATM protein kinase and cellular redox signaling: beyond the DNA damage response
Ditch, S., & Paull, T. T. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2011.10.002 · Cited by 325 · see citing works
Foxo3 is required for the regulation of oxidative stress in erythropoiesis
Marinković, D., Zhang, X., Yalcin, S., Luciano, J. P., Brugnara, C., Huber, T. L., & Ghaffari, S. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31807 · Cited by 320 · see citing works
Mechanisms that Regulate Stem Cell Aging and Life Span
Signer, R. A. J., & Morrison, S. J. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.01.001 · Cited by 320 · see citing works
Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny
Chambers, S. M., Boles, N. C., Lin, K. K., Tierney, M., Bowman, T. V., Bradfute, S. B., Chen, A. J., Merchant, A. A., Sirin, O., Weksberg, D. C., et al. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.10.003 · Cited by 318 · see citing works
“Likewise, the shared fingerprint genes are either required for the function of all family cell types, such as Atm in the lymphoid fingerprint (Ito et al., 2004), or for differentiation of the cell-type family (Figure 3A).”
BackgroundMaintaining Tissue Homeostasis: Dynamic Control of Somatic Stem Cell Activity
Biteau, B., Hochmuth, C. E., & Jasper, H. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.10.004 · Cited by 310 · see citing works
“…regenerative potential and self-renewal in a wide range of SC populations, including neuronal and glial progenitors and HSCs (Diehn et al., 2009; Ito et al., 2004; Le Belle et al., 2011; Liu et al., 2009; Miyamoto et al., 2007, 2008; Smith et al., 2000; Tothova and Gilliland, 2007; Tothova et…”
InfluentialThe mitochondrial respiratory chain is essential for haematopoietic stem cell function
Ansó, E., Weinberg, S. E., Diebold, L. P., Thompson, B. J., Malinge, S., Schumacker, P. T., Liu, X., Zhang, Y., Shao, Z., Steadman, M., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3529 · Cited by 310 · see citing works
Metastasis: cancer cell’s escape from oxidative stress
Pani, G., Galeotti, T., & Chiarugi, P. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9225-4 · Cited by 312 · see citing works
“This finding extends to cancer stem cells previous discoveries on the role of intracellular ROS in governing the balance between self-renewal and differentiation of glial precursor cells [211] and of HSCs [209, 212].”
BackgroundInfluentialManifestations and mechanisms of stem cell aging
Liu, L. A., & Rando, T. A. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201010131 · Cited by 306 · see citing works
“DNA repair processes are important for maintaining stem cell homeostasis during aging, as demonstrated in several genetically modified mouse models that are defective for DNA repair (Ito et al., 2004; Ben-Porath and Weinberg, 2005; Nijnik et al., 2007; Rossi et al., 2007; Ruzankina et al., 2007).”
Yahata, T., Takanashi, T., Muguruma, Y., Ibrahim, A. A., Matsuzawa, H., Uno, T., Sheng, Y., Onizuka, M., Ito, M., Kato, S., et al. (2011) · Blood · doi:10.1182/blood-2011-01-330050 · Cited by 298 · see citing works
The Systematic Production of Cells for Cell Therapies
Kirouac, D. C., & Zandstra, P. W. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.09.001 · Cited by 300 · see citing works
“The beneficial effects on HSC expansion may therefore be mediated via autocrine and/or paracrine signaling activity in addition to reduced oxidative stress (Ito et al., 2004; Ito et al., 2006).”
BackgroundCellular functions of the protein kinase ATM and their relevance to human disease
Lee, J., & Paull, T. T. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00394-2 · Cited by 290 · see citing works
Li, L., & Bhatia, R. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1499 · Cited by 291 · see citing works
“ATM is preferentially expressed in cycling HSC, and ATM-deficient mice show elevated ROS levels, lack quiescent HSC and show progressive BM failure (14).”
Tumor suppressor genes and ROS: complex networks of interactions
Vurusaner, B., Poli, G., & Başağa, H. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.09.035 · Cited by 292 · see citing works
BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival
Gorrini, C., Baniasadi, P. S., Harris, I. S., Silvester, J., Inoue, S., Snow, B., Joshi, P. A., Wakeham, A., Molyneux, S. D., Martin, B., et al. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20121337 · Cited by 289 · see citing works
“Similarly, high oxidative stress caused by ATM deficiency triggers senescence and limits long-term in vivo repopulation of the hematopoietic compartment (Ito et al., 2004).”
BackgroundSelf-citationChanges in primary lymphoid organs with aging
Chinn, I. K., Blackburn, C. C., Manley, N. R., & Sempowski, G. D. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.005 · Cited by 282 · see citing works
“Treatment with N-acetylcysteine or catalase decreased intracellular ROS levels in HSCs and restored hematopoietic reconstitutive capacity of the cells [28], thus emphasizing the additional impact of ROS on HSC functional decline with aging.”
BackgroundRegulation of reactive oxygen species in stem cells and cancer stem cells
Kobayashi, C. I., & Suda, T. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22764 · Cited by 290 · see citing works
“Ito et al. (2008) demonstrated the critical role of the promyelocytic leukemia protein (PML) tumor suppressor in the maintenance of quiescent CML stem cells, introducing the possibility of eradicating CML stem cells with arsenic trioxide (As2O3) (Ito et al., 2008), a ROS generator that inhibits PML.”
BackgroundSelf-citationMolecular pathogenesis and clinical management of Fanconi anemia
Kee, Y., & D’Andrea, A. D. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58321 · Cited by 284 · see citing works
“Such hypersensitivity may lead to decreased hematopoietic cellularity (stem cell loss in early development), similar to phenotypes observed in ATM-deficient or ligase IV–deficient (LIG4-deficient) mice (102, 103).”
The role of mitochondria in stem cell fate and aging
Zhang, H., Menzies, K. J., & Auwerx, J. H. (2018) · Development · doi:10.1242/dev.143420 · Cited by 285 · see citing works
“Mice with mutations in the DNA damage sensor ataxia telangiectasia (ATM) show a defect in HSC function that is associated with elevated ROS production, and treatment with the anti-oxidant N-acetyl-L-cysteine (NAC) restored HSC function in these mice (Ito et al., 2004).”
Background
- Authors
- Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., Ikeda, Y., Mak, T. W., & Suda, T.
- Affiliations
- Keio University (JP)
- Kumamoto University (JP)
- University of Toronto (CA)
- Corresponding author
- Hirao, Atsushi
- Suda, Toshio
- ORCID
- Venue
- Nature
- Published
- 2004-10
- Volume
- 431
- Issue
- 7011
- Pages
- 997-1002
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2041897873
- Cited by
- 1,175
- References
- 30
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 38 · 2023: 31 · 2022: 37 · 2021: 51 · 2020: 44 · 2019: 58 · 2018: 47 · 2017: 59 · 2016: 73 · 2015: 71 · 2014: 75 · 2013: 88 · 2012: 77
- FWCI
- 25.91
- 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 › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ATM, oxidative stress, hematopoietic stem cells, self-renewal, reactive oxygen species, ataxia telangiectasia, bone marrow failure, p16INK4a, retinoblastoma protein, DNA damage response, antioxidant therapy
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, Cell Division, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Retinoblastoma Protein, Protein Serine-Threonine Kinases, Gene Deletion, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Cell Cycle Proteins, Cell Lineage, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, Mice, Ataxia Telangiectasia Mutated Proteins
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