Whole body proton irradiation causes acute damage to bone marrow hematopoietic progenitor and stem cells in mice

Abstract

Purpose: Exposure to proton irradiation during missions in deep space can lead to bone marrow injury. The acute effects of proton irradiation on hematopoietic stem and progenitor cells remain undefined and thus were investigated.

Materials and methods: We exposed male C57BL/6 mice to 0.5 and 1.0 Gy proton total body irradiation (proton-TBI, 150 MeV) and examined changes in peripheral blood cells and bone marrow (BM) progenitors and LSK cells 2 weeks after exposure.

Results: 1.0 Gy proton-TBI significantly reduced the numbers of peripheral blood cells compared to 0.5 Gy proton-TBI and unirradiated animals, while the numbers of peripheral blood cell counts were comparable between 0.5 Gy proton-TBI and unirradiated mice. The frequencies and numbers of LSK cells and CMPs in BM of 0.5 and 1.0 Gy irradiated mice were decreased in comparison to those of normal controls. LSK cells and CMPs and their progeny exhibited a radiation-induced impairment in clonogenic function. Exposure to 1.0 Gy increased cellular apoptosis but not the production of reactive oxygen species (ROS) in CMPs two weeks after irradiation. LSK cells from irradiated mice exhibited an increase in ROS production and apoptosis.

Conclusion: Exposure to proton-TBI can induce acute damage to BM progenitors and LSK cells.

Keywords:

• Proton irradiation
• hematopoietic stem cells
• apoptosis
• reactive oxygen species

Acknowledgements

The study was supported in part by the National Space Biomedical Research Institute through NCC 9-58, Centers of Biomedical Research Excellence [P20, GM109005], Arkansas Research Alliance Scholarship, and Rockefeller Leukemia and Lymphoma Research Endowment.

Disclosure statement

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

Notes on contributors

Jianhui Chang, his research focuses on radiation-induced senescence of hematopoietic stem cells and muscle stem cells using mice models. He is investigating how to deplete these senescent stem cells induced by irradiation.

Yingying Wang, her research focuses on the molecular mechanisms which might cause cellular senescence, contributing to investigate different strategies to deplete senescent cells in vitro and in vivo.

Rupak Pathak, his current research interest is radiation-induced normal tissue injury particularly radiation-induced endothelial dysfunction and genomic instability using FISH-based molecular techniques. One of the major research goals is to develop radiation countermeasures that can be used in the event of accidental or incidental radiation mass casualty.

Vijayalakshmi Sridharan, her research focuses on the interactions between ionizing radiation and normal tissues, particularly the molecular mechanisms that lead to the development of radiation-induced heart disease and the identification of potential treatments.

Tamako Jones, her research interest is the effects of charged particle radiations on the hematopoietic system using irradiated mice models.

Xiao Wen Mao, her research interest is to evaluate an antioxidant compound to protect the normal tissue, including normal vasculature, from radiation-induced damage. This agent can be considered for translational studies to use in radiation therapy as a therapeutic radio-protector.

Gregory Nelson, his current research interests center on the effects of ionizing radiation on normal cells and tissues. He is investigating functional consequences of radiation exposure with emphasis on charged particle radiations such as protons. His interests in astronaut health extend to effects of weightlessness and have involved experiments flown on five space shuttle missions.

Marjan Boerma, her research focuses on cancer survivorship issues, particularly radiation-induced heart disease, risks of cardiovascular disease from exposure to radiation during space travel, and development of medical countermeasures against nuclear accidents or terrorism.

Martin Hauer-Jensen, his research focuses on cancer survivorship issues, particularly on how to make radiation therapy more tolerable, safer, and more effective, and on development of medical countermeasures against radiological/nuclear accidents or terrorism.

Daohong Zhou, his research focuses on radiation and chemotherapy induced hematopoietic stem cell injury and leukemia and on development of mechanism-based strategies to protect the hematopoietic system from cancer therapy-induced damage and novel medical countermeasures against radiological/nuclear accidents or terrorism.

Lijian Shao, his research focuses on radiation-induced long term hematopoietic stem cell injury and on understanding the molecular mechanisms of residual stem cell damage after exposure to radiation. His goal is to development of medical countermeasures against radiation-induced hematopoietic injury in cancer patients.

Additional information

Funding

National Space Biomedical Research Institute10.13039/100008898NCC 9-58

Centers of Biomedical Research ExcellenceP20, GM109005

The study was supported in part by the National Space Biomedical Research Institute through NCC 9-58, Centers of Biomedical Research Excellence [P20, GM109005], Arkansas Research Alliance Scholarship, and Rockefeller Leukemia and Lymphoma Research Endowment.