Ionizing radiation induces ferroptosis in granulocyte-macrophage hematopoietic progenitor cells of murine bone marrow

Abstract

Purpose: To study whether radiation-induced bleeding in the bone marrow induced iron accumulation, and subsequently caused ferroptosis in granulocyte-macrophage hematopoietic progenitor cells.

Materials and methods: Male mice were subjected to different doses (0, 4, 8, or 10 Gy) of gamma radiation from a ¹³⁷Cs source. The changes in iron metabolism or ferroptosis-related parameters of irradiated bone marrow were accessed with biochemical, histopathological, and antibody methods. Hematocytes were detected with a hematology analyzer. The counts of granulocyte-macrophage hematopoietic progenitor cells were measured with the granulocyte-macrophage colony-forming unit.

Results: Iron accumulation occurred in the bone marrow, which caused by radiation-induced hemorrhage. The iron accumulation triggered an iron regulatory protein-ferroportin 1 axis to increase serum iron levels. Using LDN193189, radiation-induced iron accumulation was demonstrated to decrease white blood cell counts at least partly through a decrease in the counts of granulocyte-macrophage hematopoietic progenitor cells. The reduction in the counts of granulocyte-macrophage hematopoietic progenitor cells was subsequently demonstrated to attribute to ferroptosis with the use of ferroptosis inhibitors and through the detection of ferroptosis related-parameters. The survival rate of irradiated mice was improved using Ferrostatin-1 or LDN193189.

Conclusions: These findings suggest that radiation-induced hemorrhage in the bone marrow causes ferroptosis in granulocyte-macrophage hematopoietic progenitor cells, and anti-ferroptosis has the potential to be a radioprotective strategy to ameliorate radiation-induced hematopoietic injury.

Graphical Abstract

Keywords:

• Hematopoietic acute radiation sickness
• ferroptosis
• iron accumulation
• iron metabolism

Disclosure statement

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

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant [numbers 11575086, 11705089, 11775115, and 81571805]; the Postdoctoral Science Foundation of China under Grant [number 2017M611660]; and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Notes on contributors

Xiaohong Zhang

Xiaohong Zhang, PhD. She is a senior experimentalist in the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the areas of radiation biology and biodosimetry.

Xueshuang Xing

Xueshuang Xing, MD. She is a postgraduate in the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of radiation biology.

Huiwen Liu

Huiwen Liu, MD. She is a postgraduate in the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of radiation biology.

Jundong Feng

Jundong Feng, PhD. She is an associate professor in the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of space radiation protection.

Mengxin Tian

Mengxin Tian, MD. She is a postgraduate in the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. Her research interests are in the area of radiation biology.

Shuquan Chang

Shuquan Chang, PhD. He is the head of the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. His research interests are in the area of radiation protection.

Peidang Liu

Peidang Liu, PhD. He is an associate professor of the Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University. His research interests are in the areas of radiation biology and radiotherapy.

Haiqian Zhang

Haiqian Zhang, PhD. He is a professor in the Department of Nuclear Science and Technology, Nanjing University of Aeronautics and Astronautics. His research interests are in the area of radiation protection.