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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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In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
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 [20]
In the citing paper
“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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“Abbreviations 7 + 3 7 days of cytarabine, 3 days of an anthracycline antibiotic ALL Acute lymphoblastic leukaemia AML Acute myeloid leukaemia APL Acute promyelocytic leukaemia ATM Ataxia telangiectasia mutated ATO Arsenic trioxide BCL2 B-cell lymphoma 2 CD34+ Marker of human HSC CML chronic myeloid leukaemia DUOX Dual…”
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Szade, K., Gulati, G. S., Chan, C. K. F., Kao, K. S., Miyanishi, M., Marjon, K. D., Sinha, R., George, B. M., Chen, J. Y., & Weissman, I. L. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7419 · Cited by 145
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“This manifests as a reduced reconstitutive capacity and progressive BM failure reminiscent of Ercc1 / mice (Ito et al, 2004).”
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“Murine ESCs exhibited low levels of intracellular ROS compared to differentiated murine cells, due to the increased level of GSH and thioredoxin (TXN) system [41].”
BackgroundTargeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease
Cianflone, E., Torella, M., Biamonte, F., Angelis, A. D., Urbanek, K., Costanzo, F. S., Rota, M., Ellison, G. M., & Torella, D. (2020) · Cells · doi:10.3390/cells9061558 · Cited by 137
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“ATM also regulates the maintenance of hematopoietic stem cells (Ito et al. 2004).”
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“HSCs from ATM-deficient mice displayed increased ROS levels and a concomitant decrease in functional capacity which could be rescued by administration of the antioxidant N-acetyl-L-cysteine (NAC) (Ito et al., 2004).”
Nrf2 Regulates Neurogenesis and Protects Neural Progenitor Cells Against Aβ Toxicity
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“They also show increased levels of tumor suppressors proteins including p16 and p19 [41].”
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“RNS) during regeneration and repair have not been clearly established, several recent reports on hematopoietic stem cells (HSCs) and neural stem cells (NSCs) support the notion that ROS profoundly affects adult stem cell function by modulating the self-renewal, proliferation, and differentiation potential of these cel…”
Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair
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“For example, loss of the NHEJ factor 53BP1 alleviates stress and a progressive loss of the HSC pool with age (Ito et al., 2004).”
BackgroundWang, C., Shao, L., Pan, C., Ye, J., Ding, Z., Wu, J., Du, Q., Ren, Y., & Zhu, C. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1265-2 · Cited by 126
Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice
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“This was accomplished by flow cytometric analysis of γH2AX staining in HSCs, because γH2AX staining has been widely used as a surrogate for DNA DSBs.”
BackgroundInfluentialFGF-2 suppresses cellular senescence of human mesenchymal stem cells by down-regulation of TGF-β2
Ito, T., Sawada, R., Fujiwara, Y., Seyama, Y., & Tsuchiya, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.05.067 · Cited by 125
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TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress
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“It is well established that reactive oxygen species (ROS) can play a regulatory role in hematopoiesis (Haneline, 2008; Ito et al., 2004; Ito et al., 2006; Jang and Sharkis, 2007; Lewandowski et al., 2010).”
BackgroundComplementary functions of ATM and H2AX in development and suppression of genomic instability
Zha, S., Sekiguchi, J., Brush, J. W., Bassing, C. H., & Alt, F. W. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803520105 · Cited by 121
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Metabolic regulation of the hallmarks of stem cell biology
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“In Atm / HSCs, activation of the p16Ink4a- pRb cascade underlies stem cell exhaustion (Ito et al., 2004).”
BackgroundResultSelf-citationATM directs DNA damage responses and proteostasis via genetically separable pathways
Lee, J., Mand, M. R., Kao, C.-H., Zhou, Y., Ryu, S. W., Richards, A., Coon, J. J., & Paull, T. T. (2018) · Science Signaling · doi:10.1126/scisignal.aan5598 · Cited by 122
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“Although an emerging number of studies have suggested that ROS and ROS-related factors influence the development, self-renewal, migration, and differentiation of HSCs (145, 148, 149, 153, 286), HSCs have been demonstrated to express various redox enzymes (284, 286, 353) at relatively low levels.”
BackgroundATM protein kinase: the linchpin of cellular defenses to stress
Bhatti, S., Kozlov, S., Farooqi, A. A., Naqi, A., Lavin, M., & Khanna, K. K. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0683-9 · Cited by 116
“Ito et al. (2004) [239] discovered that ATM can protect hematopoietic stem cells (HSC) from oxidative stress damage and allow them to maintain their self-renewal potential.”
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Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction
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“ATM could also be critical for apoptosis and for maintaining the progenitor cell phenotype [42].”
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“Regulators of ROS, cell cycle, and apoptosis play important roles in HSC self-renewal and maintenance under homeostatic conditions and in responses to genotoxic stressors such as radiation (2, 14, 43, 52, 53).”
Biology of Normal and Acute Myeloid Leukemia Stem Cells
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“Although recent studies have identified the murine HSC niche and the central role in the endosteum region of bone-forming osteoblasts, which support stem cells via notch, � -catenin, and Tie-2 signaling [ 67-69 ], little is known about the human stem cell niche in the adult BM, let alone the leukemic niche.”
BackgroundHatori, Y., Yan, Y., Schmidt, K., Furukawa, E., Hasan, N. M., Yang, N., Liu, C.-N., Sockanathan, S., & Lutsenko, S. (2016) · Nature Communications · doi:10.1038/ncomms10640 · Cited by 110
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Self-citationStem Cells, Redox Signaling, and Stem Cell Aging
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“Specifically, alterations in the regulation of ROS by FoxO3 and ATM with age contribute to HSC aging (47, 48, 70).”
InfluentialImmunoaging induced by hematopoietic stem cell aging
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“This concept is supported by the premature HSC exhaustion observed in mice deficient for the oxidative stress mediators ATM or FoxO (Ito et al. 2004; Tothova et al. 2007).”
BackgroundInflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence
Zhang, X., Sejas, D. P., Qiu, Y., Williams, D. A., & Pang, Q. (2007) · Journal of Cell Science · doi:10.1242/jcs.003152 · Cited by 114
“…anemia (FA) shares the common feature of having defective DNA damage response/repair processes with other premature aging syndromes such as Bloom (Bischof et al., 2001) and Werner (Chen et al., 2003), ataxia telangiectasia (Ito et al., 2004) and BRCA1-deficient breast cancer (Cao et al., 2003).”
BackgroundDifferential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBSPreprint
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“Additionally, both ATM and NBS1 can function in stem and progenitor populations in the hematopoeitic and germ cell compartments (Kang et al. 2002; Ito et al. 2004; Takubo et al. 2008).”
BackgroundBreast Cancer Stem Cells: Current Advances and Clinical Implications
Luo, M., Clouthier, S. G., Deol, Y. S., Liu, S., Nagrath, S., Azizi, E., & Wicha, M. S. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2519-3_1 · Cited by 106
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“GSH was shown to be a critical cellular reducing agent and antioxidant that is responsible for reducing ROS levels.”
BackgroundInfluentialMitochondrial Role in Stemness and Differentiation of Hematopoietic Stem Cells
Papa, L., Djedaini, M., & Hoffman, R. (2019) · Stem Cells International · doi:10.1155/2019/4067162 · Cited by 108
“HSCs are particularly vulnerable to oxidative stress and high levels of ROS [12, 13].”
BackgroundHematopoietic Dysfunction in a Mouse Model for Fanconi Anemia Group D1
Navarro, S., Meza, N. W., Bustamante, O. Q., Casado, J. A., Jacome, A., McAllister, K. A., Puerto, S., Surrallés, J., Segovia, J. C., & Bueren, J. A. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.05.018 · Cited by 110
“In this respect, mice with mutations in proteins involved in doublestrand break (DSB) repair, like Rad50 [1] and Atm / mice[2], developed a progressive hematopoietic failure resulting from a defect in the HSC function.”
BackgroundZhang, Y., Dépond, M., He, L., Foudi, A., Kwarteng, E. O., Lauret, E., Plo, I., Desterke, C., Dessen, P., Fujii, N., et al. (2016) · Scientific Reports · doi:10.1038/srep37827 · Cited by 108
“BSO was previously shown to promote oxidative stress in HSCs thus shortening their lifespan 12,34,35 .”
Nutrient Sensing and the Oxidative Stress Response
Luo, H., Chiang, H.-H., Louw, M., Susanto, A., & Chen, D. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.02.008 · Cited by 107
“Increased ROS production due to aberrant activation of the TSC-mTOR pathway [52, 76] or defective DNA damage response [77, 78], failure to engage the oxidative stress response resulting from defective FOXOs, SIRT3, Nrf2, or thioredoxinLuo et al.”
BackgroundMetabolic reprograming of anti-tumor immunity
Sukumar, M., Kishton, R. J., & Restifo, N. P. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.03.011 · Cited by 103
Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity
Zhang, Y., Lee, J., Paull, T. T., Gehrke, S. A., D’Alessandro, A., Dou, Q., Gladyshev, V. N., Schroeder, E. A., Steyl, S. K., Christian, B. E., et al. (2018) · Science Signaling · doi:10.1126/scisignal.aaq0702 · Cited by 104
Osteolineage niche cells initiate hematopoietic stem cell mobilization
Mayack, S. R., & Wagers, A. J. (2008) · Blood · doi:10.1182/blood-2008-01-133710 · Cited by 102
RetractedHypoxia and Senescence: The Impact of Oxygenation on Tumor Suppression
Welford, S. M., & Giaccia, A. J. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0065 · Cited by 103
“It is tempting to think then that these cells, which are known to be more resistant to oxidative stress as a mechanism of self-preservation (84, 85), benefit from their hypoxic environments by avoiding senescence, which would be detrimental to the regenerative capacity of the tissue.”
BackgroundKruta, M., Sunshine, M. J., Chua, B. A., Fu, Y., Chawla, A., Dillingham, C. H., Hidalgo San Jose, L., De Jong, B., Zhou, F. J., & Signer, R. A. J. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.07.009 · Cited by 100
Nijnik, A., Clare, S., Hale, C., Raisen, C. L., McIntyre, R. E., Yusa, K., Everitt, A. R., Mottram, L., Podrini, C., Lucas, M., et al. (2011) · Blood · doi:10.1182/blood-2011-05-352666 · Cited by 106
Yin, T., Wang, G., He, S., Liu, Q., Sun, J., & Wang, Y. (2015) · Cellular Immunology · doi:10.1016/j.cellimm.2015.11.009 · Cited by 99
Bone Marrow Niches of Hematopoietic Stem and Progenitor Cells
Kandarakov, O. F., Belyavsky, A. V., & Semenova, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084462 · Cited by 107
“In addition to AKT1 and AKT2, ROS levels in HSCs are regulated by ATM [148] and the Foxo transcription factor family [149,150].”
BackgroundRedox Regulation and Its Emerging Roles in Stem Cells and Stem-Like Cancer Cells
Ogasawara, M. A., & Zhang, H. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2308 · Cited by 98
Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells
Liu, X., Li, F., Huang, Q., Zhang, Z., Zhou, L., Deng, Y., Zhou, M., Fleenor, D. E., He, W., Kastan, M. B., et al. (2017) · Cell Research · doi:10.1038/cr.2017.41 · Cited by 99
Asada, A., Nishida, A., Shioya, M., Imaeda, H., Inatomi, O., Bamba, S., Kito, K., Sugimoto, M., & Andoh, A. (2015) · Journal of Gastroenterology · doi:10.1007/s00535-015-1142-4 · Cited by 96
“Acute bone marrow suppression is the result of the induction of apoptosis in the proliferating bone marrow stem cells, and several studies have shown that the induction of oxidative stress is primarily responsible for the loss of bone marrow- and hair follicle-stem cells [31–33].”
BackgroundZhan, H., Suzuki, T., Aizawa, K., Miyagawa, K., & Nagai, R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.125138 · Cited by 101
Aging and Regeneration in Vertebrates
Sousounis, K., Baddour, J., & Tsonis, P. A. (2014) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-391498-9.00008-5 · Cited by 96
Pharmacological Regulation of Oxidative Stress in Stem Cells
Lee, J., Cho, Y. S., Jung, H., & Choi, I. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/4081890 · Cited by 99
“Increased ROS levels enhance the cycling of HSCs and promote the exhaustion of the stem cell pool [81, 82].”
BackgroundInfluentialmTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells
Guo, F., Li, J., Du, W., Zhang, S., O’Connor, M. P., Thomas, G., Kozma, S. C., Zingarelli, B., Pang, Q., & Zheng, Y. (2013) · Leukemia · doi:10.1038/leu.2013.93 · Cited by 91
Hematopoietic stem cell fate through metabolic control
Ito, K., & Ito, K. (2018) · Experimental Hematology · doi:10.1016/j.exphem.2018.05.005 · Cited by 98
Self-citationHematopoietic Stem Cell Aging: Wrinkles In Stem Cell Potential
Chambers, S. M., & Goodell, M. A. (2007) · Stem Cell Reviews and Reports · doi:10.1007/s12015-007-0027-1 · Cited by 92
“First, in young mice, a defect of ataxia telangiectasia mutated (ATM), a gene essential for DNA repair, results in a dramatic failure of HSC function [59].”
Toward an Understanding of the Physiological Function of Mammalian Stem Cells
Joseph, N. M., & Morrison, S. J. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.07.001 · Cited by 94
de Laval, B., Pawlikowska, P., Petit, L., Bilhou‐Nabera, C., Aubin‐Houzelstein, G., Souyri, M., Pouzoulet, F., Gaudry, M., & Porteu, F. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.10.012 · Cited by 104
“Maintenance of genomic integrity is also crucial for preservation of HSC self-renewal (Ito et al., 2004; Nijnik et al., 2007; Rossi et al., 2007).”
BackgroundThe role of DNA repair in the pluripotency and differentiation of human stem cells
Rocha, C. R. R., Lerner, L. K., Okamoto, O. K., Marchetto, M. C., & Menck, C. F. M. (2012) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2012.09.001 · Cited by 94
Rodrigues-Moreira, S., Moreno, S. G., Ghinatti, G., Lewandowski, D., Hoffschir, F., Ferri, F., Gallouët, A.-S., Gay, D. L., Motohashi, H., Yamamoto, M. P., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.013 · Cited by 99
Strategies for Isolating and Enriching Cancer Stem Cells: Well Begun Is Half Done
Duan, J., Qiu, W., Xu, S., Wang, B., Ye, X.-Z., Ping, Y., Zhang, X., Bian, X., & Yu, S. (2013) · Stem Cells and Development · doi:10.1089/scd.2012.0613 · Cited by 90
Trafficking from the bone marrow to the thymus: a prerequisite for thymopoiesis
Schwarz, B. A., & Bhandoola, A. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00350.x · Cited by 97
“This idea is supported by a recent study of mice lacking the gene for ataxia telangiectasia mutated (Atm), a gene activated in response to oxidative stress (29).”
ResultHoebeke, I., Smedt, M. D., Stolz, F., Pike‐Overzet, K., Staal, F. J. T., Plum, J. R., & Leclercq, G. (2006) · Leukemia · doi:10.1038/sj.leu.2404488 · Cited by 89
Mechanisms of hematopoietic stem cell aging
Ergen, A. V., & Goodell, M. A. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2009.12.010 · Cited by 93
Glutathione peroxidases as oncotargets
Jiao, Y., Wang, Y., Guo, S., & Wang, G. (2017) · Oncotarget · doi:10.18632/oncotarget.20278 · Cited by 92
“Most Atm knockout mice die at early, whereas a small percentage of mice survive [69].”
BackgroundNiwa, O., Barcellos‐Hoff, M. H., Globus, R. K., Harrison, J. D., Hendry, J. H., Jacob, P., Martin, M. T., Seed, T. M., Shay, J. W., Story, M. D., et al. (2015) · Annals of the ICRP · doi:10.1177/0146645315595585 · Cited by 91
“Active (red) bone marrow Bone marrow contains the cell systems for the formation of blood cells, starting from the pluripotent haematopoietic stem cells (HSCs) to the mature blood cells.”
BackgroundInfluentialProbing metabolic states of differentiating stem cells using two-photon FLIM
Meleshina, A. V., Dudenkova, V. V., Shirmanova, M. V., Shcheslavskiy, V. I., Becker, W. H., Bystrova, A. S., Cherkasova, E. I., & Вадимовна, З. Е. (2016) · Scientific Reports · doi:10.1038/srep21853 · Cited by 90
The roles of autophagy in vascular smooth muscle cells
Tai, S., Hu, X., Peng, D., Zhou, S., & Zheng, X. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.02.128 · Cited by 88
Critical Role of Jak2 in the Maintenance and Function of Adult Hematopoietic Stem Cells
Akada, H., Akada, S., Hutchison, R. E., Sakamoto, K., Wagner, K., & Mohi, G. (2014) · Stem Cells · doi:10.1002/stem.1711 · Cited by 97
Hämäläinen, R. H., Landoni, J. C., Ahlqvist, K. J., Goffart, S., Ryytty, S., Rahman, M. O., Brilhante, V., Icay, K., Hautaniemi, S., Wang, L., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0120-1 · Cited by 89
Lee, J., Lee, M., Moon, B., Shim, S. H., Fornace, A. J., & Cha, H. (2009) · Stem Cells · doi:10.1002/stem.121 · Cited by 89
Neurogenesis and Alzheimers Disease: Biology and Pathophysiology in Mice and Men
Marlatt, M. W., & Lucassen, P. J. (2010) · Current Alzheimer Research · doi:10.2174/156720510790691362 · Cited by 91
Esposito, M. T., & So, C. W. E. (2014) · Chromosoma · doi:10.1007/s00412-014-0482-9 · Cited by 88
“Recent findings indicate that AML1-ETO represses a variety of genes involved in DDR and in particular those involved in BER, such as OGG1, FEN1, MPG, POLD2, POLD3 and POLE, and ATM, one of the most important transducers of DDR (Figs.”
BackgroundInfluentialRowaiye, A. B., Okpalefe, O. A., Onuh, O. A., Ogidigo, J. O., Oladipo, O. H., Ogu, A. C., Oli, A. N., Olofinsae, S. A., Onyekwere, O., Abubakar, A. R., et al. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s301784 · Cited by 87
Regulation of emergency granulopoiesis during infection
Paudel, S., Ghimire, L., Jin, L., Jeansonne, D. P., & Jeyaseelan, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.961601 · Cited by 94
“While ROSlow-HSCs are long-term repopulating and low cell cycling, ROShigh-HSCs are short-term repopulating, cell cycling, and differentiating (102, 103).”
BackgroundQuiescence regulators for hematopoietic stem cell
Li, J. (2011) · Experimental Hematology · doi:10.1016/j.exphem.2011.01.008 · Cited by 93
“ATM deficiency-induced ROS elevation in HSCs specifically activates the p38 mitogen-activated protein kinase (MAPK) pathway, a signaling pathway responding to diverse cellular stresses, leading to a defect in the maintenance of HSC quiescence [105].”
BackgroundRomero–Moya, D., Bueno, C., Montes, R., Navarro-Montero, Ó., Iborra, F. J., López, L. C., Martı́n, M., & Menéndez, P. R. (2013) · Haematologica · doi:10.3324/haematol.2012.079244 · Cited by 86
“Various recent studies in mice have provided evidence for a link between intracellular ROS levels and preservation of stem cell function, with increased levels of ROS being associated with reduced repopulating stem cell activity.(32,33) Stem cells have strategies to lessen the negative impact of ROS such as lowering t…”
BackgroundVascular stem cells and ischaemic retinopathies
Stitt, A. W., O’Neill, C. L., O’Doherty, M., ARCHER, D. B., Gardiner, T. A., & Medina, R. J. (2011) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2011.02.001 · Cited by 86
“Oxidative stress is known to have a significant detrimental effect on HSCs (Ito et al., 2004) although, in general, stem cells have”
BackgroundUnderstanding glioma stem cells: rationale, clinical relevance and therapeutic strategies
Ahmed, A. U., Auffinger, B., & Lesniak, M. S. (2013) · Expert Review of Neurotherapeutics · doi:10.1586/ern.13.42 · Cited by 93
Metadata
- 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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