A Single Radioprotective Dose of Prostaglandin E(2) Blocks Irradiation-Induced Apoptotic Signaling and Early Cycling of Hematopoietic Stem Cells

Ionizing radiation exposure results in acute and delayed bone marrow suppression. Treatment of mice with 16,16-dimethyl prostaglandin E(2) (dmPGE(2)) prior to lethal ionizing radiation (IR) facilitates survival, but the cellular and molecular mechanisms are unclear. In this study we show that dmPGE(2) attenuates loss and enhances recovery of bone marrow cellularity, corresponding to a less severe hematopoietic stem cell nadir, and significantly preserves long-term repopulation capacity and progenitor cell function. Mechanistically, dmPGE(2) suppressed hematopoietic stem cell (HSC) proliferation through 24 h post IR, which correlated with fewer DNA double-strand breaks and attenuation of apoptosis, mitochondrial compromise, oxidative stress, and senescence. RNA sequencing of HSCs at 1 h and 24 h post IR identified a predominant interference with IR-induced p53-downstream gene expression at 1 h, and confirmed the suppression of IR-induced cell-cycle genes at 24 h. These data identify mechanisms of dmPGE(2) radioprotection and its potential role as a medical countermeasure against radiation exposure.