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Haematologica 2020 Volume 105(8):2044-2055
Hematopoiesis
Human hematopoietic stem/progenitor cells display reactive oxygen species-dependent long-term hematopoietic defects after exposure to low doses of ionizing radiations
Elia Henry,*1,2,3,4 Inès Souissi-Sahraoui,*1,2,3,4 Margaux Deynoux,1,2,3,4 Andréas Lefèvre,1,2,3,4 Vilma Barroca,1,2,3,4 Anna Campalans,3,4,5 Véronique Ménard,3,4,6 Julien Calvo,1,2,3,4 Françoise Pflumio,#1,2,3,4 and Marie-Laure Arcangeli#1,2,3,4
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INSERM, U1274, Laboratory "Niche, Cancer and Hematopoiesis"; CEA, DRF-JACOB-
IRCM-SCSR-LSHL, UMR “Genetic stability, Stem Cells and Radiation”; 3UMR “Genetic stability, Stem Cells and Radiation” Université de Paris; 4UMR “Genetic stability, Stem Cells and Radiation”, Université Paris-Saclay; 5CEA, DRF-JACOB-IRCM-SIGRR-LRIG, UMR “Genetic stability, Stem Cells and Radiation” and 6UMR “Genetic stability, Stem Cells and Radiation", F-92265 Fontenay-aux-Roses, France
*EH and IS-S contributed equally as co-first authors. #FP and M-LA contributed equally as co-senior authors.
ABSTRACT
Hematopoietic stem cells are responsible for life-long blood cell production and are highly sensitive to exogenous stresses. The effects of low doses of ionizing radiations on radiosensitive tis- sues such as the hematopoietic tissue are still unknown despite their increasing use in medical imaging. Here, we study the consequences of low doses of ionizing radiations on differentiation and self-renewal capacities of human primary hematopoietic stem/progenitor cells (HSPC). We found that a single 20 mGy dose impairs the hematopoietic reconstitution potential of human HSPC but not their differentiation properties. In contrast to high irradiation doses, low doses of irradiation do not induce DNA double strand breaks in HSPC but, similar to high doses, induce a rapid and transient increase of reactive oxygen species (ROS) that promotes activation of the p38MAPK pathway. HSPC treat- ment with ROS scavengers or p38MAPK inhibitor prior exposure to 20 mGy irradiation abolishes the 20 mGy-induced defects indicating that ROS and p38MAPK pathways are transducers of low doses of radiation effects. Taken together, these results show that a 20 mGy dose of ioniz- ing radiation reduces the reconstitution potential of HSPC suggesting an effect on the self-renewal potential of human hematopoietic stem cells and pinpointing ROS or the p38MAPK as therapeutic targets. Inhibition of ROS or the p38MAPK pathway protects human primary HSPC from low-dose irradiation toxicity.
Introduction
Hematopoietic stem cells (HSC) give rise to all blood cell types over the entire life of an organism. In adult mammals, they are located in very specific microenviron- ments of the bone marrow (BM), allowing maintenance of HSC functions.1 In humans, HSC are enriched in the CD34+ CD38low CD90+ CD45RA– cell population that also contains immature progenitors, hereafter called HSPC.2,3 Hematopoietic stem/progenitor cells (HSPC) are multipotent and mainly slow cycling cells. They possess a self-renewal potential that allows them to sustain the continuous genera- tion of blood cells. Quiescence and self-renewal are regulated by several extrinsic fac- tors, such as cytokines, extracellular matrix proteins and adhesion molecules,4,5 as well as intrinsic factors, such as transcription factors (TAL1,6-8 GATA-2, etc.9), proteins implicated in DNA damage repair pathways,10-12 and cell cycle regulators.13-15 Mutations in genes involved in DNA repair induce BM failure with exhaustion of the
Correspondence:
MARIE-LAURE ARCANGELI
marie-laure.arcangeli@inserm.fr
Received: May 14, 2019.
Accepted: November 27, 2019. Pre-published: November 28, 2019.
doi:10.3324/haematol.2019.226936
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2044
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