Abstract
Precise understanding of radiation effects is critical to develop new modalities for the prevention and treatment of radiation-induced damage. We previously reported that non-lethal doses of X-ray irradiation induce DNA damage in human hematopoietic stem and progenitor cells (HSPCs) reconstituted in NOD/Shi-scid IL2rγnull (NOG) immunodeficient mice and severely compromise their repopulating capacity. In this study, we analyzed in detail the functional changes in human HSPCs in NOG mice following non-lethal radiation. We transplanted cord blood CD34+ HSPCs into NOG mice. At 12 weeks post-transplantation, the recipients were irradiated with 0, 0.5, or 1.0 Gy. At 2 weeks post-irradiation, human CD34+ HSPCs recovered from the primary recipient mice were transplanted into secondary recipients. CD34+ HSPCs from irradiated mice showed severely impaired reconstitution capacity in the secondary recipient mice. Of interest, non-lethal radiation compromised contribution of HSPCs to the peripheral blood cells, particularly to CD19+ B lymphocytes, which resulted in myeloid-biased repopulation. Co-culture of limiting numbers of CD34+ HSPCs with stromal cells revealed that the frequency of B cell-producing CD34+ HSPCs at 2 weeks post-irradiation was reduced more than 10-fold. Furthermore, the key B-cell regulator genes such as IL-7R and EBF1 were downregulated in HSPCs upon 0.5 Gy irradiation. Given that compromised repopulating capacity and myeloid-biased differentiation are representative phenotypes of aged HSCs, our findings indicate that non-lethal ionizing radiation is one of the critical external stresses that promote aging of human HSPCs in the bone marrow niche.
Highlights
Human hematopoiesis is a critical physiological regenerative process that provisions mature blood cell lineages
In order to understand non-lethal radiation effects on human hematopoietic stem and progenitor cells (HSPCs) in vivo, we previously analyzed NOD/Shi-scid IL-2rγnull (NOG) immunodeficient mice reconstituted with human hematopoietic stem cells (HSCs) and preliminarily evaluated the effects of 0.5 and 1.0 Gy of total-body irradiation (TBI) on human HSCs [19], in which we observed that DNA damage inflicted by ionizing radiation restricts the self-renewal capacity of human HSPCs in vivo
Experimental design to investigate radiation effects on human HSPCs in vivo We previously reported that 0.5 or 1.0 Gy of X-ray TBI induced prolonged DNA damage in human HSPCs reconstituted in NOG mice and severely compromised their repopulating capacity [19]
Summary
Human hematopoiesis is a critical physiological regenerative process that provisions mature blood cell lineages. In order to understand non-lethal radiation effects on human hematopoietic stem and progenitor cells (HSPCs) in vivo, we previously analyzed NOD/Shi-scid IL-2rγnull (NOG) immunodeficient mice reconstituted with human HSCs and preliminarily evaluated the effects of 0.5 and 1.0 Gy of total-body irradiation (TBI) on human HSCs [19], in which we observed that DNA damage inflicted by ionizing radiation restricts the self-renewal capacity of human HSPCs in vivo. This humanized mouse model is useful for the evaluation of radiation effects on human hematopoiesis, including DNA damage, in the dose region where longterm effects on the hematopoietic system as well as other organs have been observed among atomic-bomb survivors [20]. Our findings demonstrate that non-lethal doses of ionizing irradiation profoundly affect the function of HSPCs in humanized mice and promote part of the aging-related phenotypes of human HSPCs in humanized mice, including compromised repopulating capacity and myeloid-biased differentiation at the expense of B lymphopoiesis
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