Low Dose Radiation Induced Senescence of Human Mesenchymal Stromal Cells and Impaired the Autophagy Process

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 Dec 30

PMID 25544750

Citations 72

Authors

Nicola Alessio

Stefania Del Gaudio

Stefania Capasso

Giovanni Di Bernardo

Salvatore Cappabianca

Marilena Cipollaro

Gianfranco Peluso

Umberto Galderisi

Affiliations

Soon will be listed here.

Abstract

Low doses of radiation may have profound effects on cellular function. Individuals may be exposed to low doses of radiation either intentionally for medical purposes or accidentally, such as those exposed to radiological terrorism or those who live near illegal radioactive waste dumpsites.We studied the effects of low dose radiation on human bone marrow mesenchymal stromal cells (MSC), which contain a subpopulation of stem cells able to differentiate in bone, cartilage, and fat; support hematopoiesis; and contribute to body's homeostasis.The main outcome of low radiation exposure, besides reduction of cell cycling, is the triggering of senescence, while the contribution to apoptosis is minimal. We also showed that low radiation affected the autophagic flux. We hypothesize that the autophagy prevented radiation deteriorative processes, and its decline contributed to senescence.An increase in ATM staining one and six hours post-irradiation and return to basal level at 48 hours, along with persistent gamma-H2AX staining, indicated that MSC properly activated the DNA repair signaling, though some damages remained unrepaired, mainly in non-cycling cells. This suggested that the impaired DNA repair capacity of irradiated MSC seemed mainly related to the reduced activity of a non-homologous end-joining (NHEJ) system rather than HR (homologous recombination).

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References

Leontieva O, Blagosklonny M . DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. Aging (Albany NY). 2011; 2(12):924-35. PMC: 3034181. DOI: 10.18632/aging.100265. View

Sperka T, Wang J, Rudolph K . DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol. 2012; 13(9):579-90. DOI: 10.1038/nrm3420. View

Mizushima N . Methods for monitoring autophagy. Int J Biochem Cell Biol. 2004; 36(12):2491-502. DOI: 10.1016/j.biocel.2004.02.005. View

Wang Y, Schulte B, Zhou D . Hematopoietic stem cell senescence and long-term bone marrow injury. Cell Cycle. 2005; 5(1):35-8. DOI: 10.4161/cc.5.1.2280. View

Cmielova J, Havelek R, Soukup T, Jiroutova A, Visek B, Suchanek J . Gamma radiation induces senescence in human adult mesenchymal stem cells from bone marrow and periodontal ligaments. Int J Radiat Biol. 2012; 88(5):393-404. DOI: 10.3109/09553002.2012.666001. View

Iglesias-Bartolome R, Gutkind J . Exploiting the mTOR paradox for disease prevention. Oncotarget. 2012; 3(10):1061-3. PMC: 3717954. DOI: 10.18632/oncotarget.712. View

Elliott M, Ravichandran K . Clearance of apoptotic cells: implications in health and disease. J Cell Biol. 2010; 189(7):1059-70. PMC: 2894449. DOI: 10.1083/jcb.201004096. View

Brenner D, Doll R, Goodhead D, Hall E, Land C, Little J . Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci U S A. 2003; 100(24):13761-6. PMC: 283495. DOI: 10.1073/pnas.2235592100. View

Liang X, So Y, Cui J, Ma K, Xu X, Zhao Y . The low-dose ionizing radiation stimulates cell proliferation via activation of the MAPK/ERK pathway in rat cultured mesenchymal stem cells. J Radiat Res. 2011; 52(3):380-6. DOI: 10.1269/jrr.10121. View

10.

Rodier F, Campisi J . Four faces of cellular senescence. J Cell Biol. 2011; 192(4):547-56. PMC: 3044123. DOI: 10.1083/jcb.201009094. View

11.

Altmeyer A, Josset E, Denis J, Gueulette J, Slabbert J, Mutter D . The mTOR inhibitor RAD001 augments radiation-induced growth inhibition in a hepatocellular carcinoma cell line by increasing autophagy. Int J Oncol. 2012; 41(4):1381-6. DOI: 10.3892/ijo.2012.1583. View

12.

Pochampally R . Colony forming unit assays for MSCs. Methods Mol Biol. 2008; 449:83-91. DOI: 10.1007/978-1-60327-169-1_6. View

13.

Jin Y, Na Y, Lee Y, An S, Lee J, Jung M . Comprehensive analysis of time- and dose-dependent patterns of gene expression in a human mesenchymal stem cell line exposed to low-dose ionizing radiation. Oncol Rep. 2007; 19(1):135-44. View

14.

Fazel R, Krumholz H, Wang Y, Ross J, Chen J, Ting H . Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med. 2009; 361(9):849-57. PMC: 3707303. DOI: 10.1056/NEJMoa0901249. View

15.

Martin L, Marples B, Lynch T, Hollywood D, Marignol L . Exposure to low dose ionising radiation: molecular and clinical consequences. Cancer Lett. 2013; 338(2):209-18. DOI: 10.1016/j.canlet.2013.05.021. View

16.

Sugrue T, Lowndes N, Ceredig R . Mesenchymal stromal cells: radio-resistant members of the bone marrow. Immunol Cell Biol. 2012; 91(1):5-11. DOI: 10.1038/icb.2012.61. View

17.

Rando T . Stem cells, ageing and the quest for immortality. Nature. 2006; 441(7097):1080-6. DOI: 10.1038/nature04958. View

18.

Debacq-Chainiaux F, Erusalimsky J, Campisi J, Toussaint O . Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009; 4(12):1798-806. DOI: 10.1038/nprot.2009.191. View

19.

Wouters B, SKARSGARD L . Low-dose radiation sensitivity and induced radioresistance to cell killing in HT-29 cells is distinct from the "adaptive response" and cannot be explained by a subpopulation of sensitive cells. Radiat Res. 1997; 148(5):435-42. View

20.

Gewirtz D . The four faces of autophagy: implications for cancer therapy. Cancer Res. 2014; 74(3):647-51. DOI: 10.1158/0008-5472.CAN-13-2966. View