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.

Keywords: Hematopoietic acute radiation sickness; ferroptosis; iron accumulation; iron metabolism.