Models of Patient-Derived Hematopoietic Stem Cell Xenografts for Assessing Individual Human Radiosensitivity

There are different approaches to assessing the individual radiosensitivity of humans. In this study, individual radiosensitivity was assessed in terms of survival and recovery of human hematopoietic stem cells (HSCs) after acute gamma irradiation of humanized mice. Immunodeficient NOD SCID mice were transplanted with cord blood HSCs intravenously or peripheral or umbilical cord blood HSCs intraosseously. The estimated D0 value for human HSCs was 1.19 Gy (95% CI 0.90 to 1.74), 0.99 Gy (95% CI 0.87 to 1.15), and 0.93 Gy (95% CI 0.61 to 1.91) for the three methods of obtaining humanized mice, respectively. For all three methods of mouse humanization, statistically similar models that describe the dependence of HSC survival on the acute gamma irradiation dose in the range of 0.5–1.5 Gy were obtained. Thus, intraosseous administration of peripheral blood HSCs to immunodeficient mice can be effectively used to assess the response of human HSCs to radiation exposure. Comparison of the HSC number (CD34+ cells) and their descendants (CD45+ cells) in nonirradiated and irradiated mice humanized with cells from the same donor on days 3 and 14 after irradiation makes it possible to evaluate the processes of radiation-induced death and recovery of HSCs. A coefficient calculated as the ratio of the proportion of HSCs among all human cells in the bone marrow of humanized mice on the 14th day to the proportion of HSCs on the third day after irradiation was proposed to assess the response to radiation exposure. This coefficient had an inverse linear dependence on the radiation dose, which differed in mice with increased and normal radiosensitivity and increased with the use of the radioprotector cysteamine in humanized mice. We propose to use this coefficient for a comparative assessment of human radiosensitivity.