Radiation-induced bystander effects impair transplanted human hematopoietic stem cells via oxidative DNA damage

Abstract Total body irradiation (TBI) is commonly used in host conditioning regimens for human hematopoietic stem cell (HSC) transplantation to treat various hematological disorders. Exposure to TBI not only induces acute myelosuppression and immunosuppression but also impairs the various components of the HSC niche in recipients. Our previous study demonstrated that radiation-induced bystander effects (RIBE) of irradiated recipients decreased the long-term repopulating ability of transplanted mouse HSCs. However, RIBE on human HSCs have not been studied. Here, we report that RIBE on transplanted human hematopoietic cells impaired the long-term hematopoietic reconstitution of human HSCs as well as the colony-forming ability of human hematopoietic progenitor cells (HPCs). Our further studies found that the RIBE-affected human hematopoietic cells showed enhanced DNA damage responses, cell cycle arrest and p53-dependent apoptosis, mainly due to oxidative stress. Moreover, multiple antioxidants could mitigate these bystander effects, though at different efficacies both in vitro and in vivo. Taken together, these findings suggest that RIBE impairs human HSCs by oxidative DNA damage. This study provides definitive evidence for RIBE in transplanted human HSCs and further justifies the necessity for conducting clinical trials to assess the ability of multiple antioxidants to improve the efficacy of HSC transplantation for patients with hematological or non-hematological disorders.