TY - JOUR
T1 - Low-Dose Irradiation Promotes Persistent Oxidative Stress and Decreases Self-Renewal in Hematopoietic Stem Cells
AU - Rodrigues-Moreira, Sarah
AU - Moreno, Stéphanie G.
AU - Ghinatti, Giulia
AU - Lewandowski, Daniel
AU - Hoffschir, Françoise
AU - Ferri, Federica
AU - Gallouet, Anne Sophie
AU - Gay, Denise
AU - Motohashi, Hozumi
AU - Yamamoto, Masayuki
AU - Joiner, Michael C.
AU - Gault, Nathalie
AU - Romeo, Paul Henri
N1 - Funding Information:
The authors thank J. Baijer, N. Dechamps, and S. Guenounou (CEA IDMIT, France) for their excellent technical assistance in cell sorting; V. Neuville, J. Tilliet, and V. Barroca for their help with mouse experiments; and J.-B. Lahaye and J. Bernardino-Sgherri for their technical assistance with irradiation. The authors thank M. Boher (Plate-forme GENOMIC, Institut Cochin) for technical assistance during microarray experiments. The authors thank Pr. H.R. Rodewald (Heidelberg, Germany) for kindly providing Rag2 −/− γc −/− ckit W/Wv mice; Dr. J.-P. De Villartay (INSERM UMR S1163, France) for kindly providing Cernunnos −/− mice, and Dr. C. Carles for helpful discussions on the manuscript. This work was supported by INSERM , the CEA , University Paris-Diderot , University Paris-Sud , the EDF , and the EU Euratom 7th Framework Programme RISK-IR (grant 323267 ).
PY - 2017/9/26
Y1 - 2017/9/26
N2 - Despite numerous observations linking protracted exposure to low-dose (LD) radiation and leukemia occurrence, the effects of LD irradiation on hematopoietic stem cells (HSCs) remain poorly documented. Here, we show that adult HSCs are hypersensitive to LD irradiation. This hyper-radiosensitivity is dependent on an immediate increase in the levels of reactive oxygen species (ROS) that also promotes autophagy and activation of the Keap1/Nrf2 antioxidant pathway. Nrf2 activation initially protects HSCs from the detrimental effects of ROS, but protection is transient, and increased ROS levels return, promoting a long-term decrease in HSC self-renewal. In vivo, LD total body irradiation (TBI) does not decrease HSC numbers unless the HSC microenvironment is altered by an inflammatory insult. Paradoxically, such an insult, in the form of granulocyte colony-stimulating factor (G-CSF) preconditioning, followed by LD-TBI facilitates efficient bone marrow transplantation without myeloablation. Thus, LD irradiation has long-term detrimental effects on HSCs that may result in hematological malignancies, but LD-TBI may open avenues to facilitate autologous bone marrow transplantation. Rodrigues-Moreira et al. show that low-dose irradiation induces long-term oxidative stress and decreased self-renewal capacity in hematopoietic stem cells (HSCs). LD total body irradiation after an inflammatory insult decreases HSC numbers but facilitates autologous bone marrow transplantation without myeloablation.
AB - Despite numerous observations linking protracted exposure to low-dose (LD) radiation and leukemia occurrence, the effects of LD irradiation on hematopoietic stem cells (HSCs) remain poorly documented. Here, we show that adult HSCs are hypersensitive to LD irradiation. This hyper-radiosensitivity is dependent on an immediate increase in the levels of reactive oxygen species (ROS) that also promotes autophagy and activation of the Keap1/Nrf2 antioxidant pathway. Nrf2 activation initially protects HSCs from the detrimental effects of ROS, but protection is transient, and increased ROS levels return, promoting a long-term decrease in HSC self-renewal. In vivo, LD total body irradiation (TBI) does not decrease HSC numbers unless the HSC microenvironment is altered by an inflammatory insult. Paradoxically, such an insult, in the form of granulocyte colony-stimulating factor (G-CSF) preconditioning, followed by LD-TBI facilitates efficient bone marrow transplantation without myeloablation. Thus, LD irradiation has long-term detrimental effects on HSCs that may result in hematological malignancies, but LD-TBI may open avenues to facilitate autologous bone marrow transplantation. Rodrigues-Moreira et al. show that low-dose irradiation induces long-term oxidative stress and decreased self-renewal capacity in hematopoietic stem cells (HSCs). LD total body irradiation after an inflammatory insult decreases HSC numbers but facilitates autologous bone marrow transplantation without myeloablation.
KW - bone marrow transplantation
KW - hematopoietic stem cell
KW - low-dose irradiation
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U2 - 10.1016/j.celrep.2017.09.013
DO - 10.1016/j.celrep.2017.09.013
M3 - Article
C2 - 28954235
AN - SCOPUS:85029887863
VL - 20
SP - 3199
EP - 3211
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 13
ER -