The Acute Radiation Syndrome-Mitigator Romiplostim and Secreted Extracellular Vesicles Improved Survival in Mice Exposed to Myelosuppressive Doses of Ionizing Radiation

Introduction: There is a growing concern about the risk of exposure to acute and lethal doses of ionizing radiation due to terrorist attacks and the recent threat of nuclear weapons. In the event of a radiological or nuclear public health emergency, several thousand people suffer severe injuries from radiation exposure, which can lead to acute radiation syndrome (ARS). Thus, there is a grave need for therapeutic strategies to ameliorate ARS and save the lives of survivors. It was reported that the thrombopoietin receptor agonist romiplostim (RP) has the potential to rescue mice exposed to lethal total-body ionizing radiation (TBI). However, the detailed action mechanism of the radio-mitigative and life-saving effects of RP remains unclear. This study focused on the extracellular vesicles (EVs), which are involved in cell-to-cell communication, because the mechanism of RP action may be related to EVs that reflect the radio-mitigative information. Methods: Female C57BL/6 mice exposed to lethal TBI were treated with RP, and the EVs were isolated from the serum and intraperitoneally injected into other mice with severe ARS. Results: The 30-day survival rate of mice subjected to lethal TBI with 6.5 Gy of X-rays drastically improved by 50-100% with the administration of EVs in the sera collected weekly from the mice in which radiation damage was alleviated, and the administration of RP avoided mortality. Four responsive microRNAs, namely, miR-144-5p, miR-3620-5p, miR-6354, and miR-7686-5p, showed significant expression changes in an array analysis. In particular, miR-144- 5p was expressed only in the EVs of RP-treated TBI mice. Conclusion: Specific EVs may exist in the circulating blood of mice that escaped mortality with an ARS mitigator, and their endogenous molecules may be the key to the survival of mice with severe ARS.