Compromised hematopoiesis and increased DNA damage following non-lethal ionizing radiation of a human hematopoietic system reconstituted in immunodeficient mice

Abstract

Purpose: Precise understanding of radiation effects is critical to development of new modalities for the prevention and treatment of radiation-induced damage. In this study, we evaluated the effects of non-lethal doses of X-ray irradiation on human hematopoietic stem and progenitor cells (HSPC) reconstituted in NOD/Shi-scid, IL2Rγnull (NOG) immunodeficient mice.Materials and methods: We transplanted cord blood CD34+ HSPC into NOG mice irradiated with 2.0 Gy via tail veins. At the 12th week after transplantation, the NOG mice were irradiated with 0, 0.5, 1.0, 2.0, or 4.0 Gy, and the radiation effects on human HSPC in vivo were evaluated.Results: Although a majority of the mice irradiated with 2.0 Gy or more died in 12 weeks after irradiation, the mice that were exposed to 0.5 or 1.0 Gy of irradiation survived and were subjected to analysis. The chimerism of human CD45+ hematopoietic cells in peripheral blood and bone marrow (BM) of the recipient mice was reduced in an X-ray dose-dependent manner after irradiation. Percentages of human CD34+ HSPC as well as human CD34+CD38− HSC in BM similarly declined. CD34+CD38− HSC purified from the humanized mice at the 12th week after irradiation showed significantly increased numbers of phosphorylated H2AX (γH2AX) foci, a marker of DNA breaks, in an X-ray dose- dependent manner. Expression of p16INK4A, a hallmark of aging of HSC, was also detected only in HSPC from irradiated mice.Conclusions: With further refinement, the humanized mouse model might be effectively used to study the biological effects of non-lethal radiation in vivo.