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, IL2Rγ^null (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.

Keywords::

• Human HSPC
• radiation effect
• DNA damage
• NOG immunodeficient mice

View correction statement:

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

Acknowledgements

We thank Makiko Yui for technical assistance. The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan, is a private, nonprofit foundation funded by the Japanese Ministry of Health, Labor, and Welfare and the U.S. Department of Energy, the latter in part through DOE Award DE-HS0000031 to the National Academy of Sciences.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported in part by the U.S. National Institute of Allergy and Infectious Diseases (NIAID Contract HHSN272200900059C). The views of the authors do not necessarily reflect those of the two governments.