Pharmacological targeting of luteinizing hormone-releasing hormone receptor promotes survival after lethal irradiation

Sex steroid inhibition (SSI) is a well-described strategy to promote lymphopoiesis in the bone marrow and thymus of aged and immunodepleted mice. Although the precise mechanisms underlying this regenerative effect are unclear, there is increasing evidence that sex hormones can have a profound impact on hematopoietic stem cell (HSC) function. Here we show that SSI induced by a novel class of Luteinizing Hormone-Releasing Hormone Receptor antagonist (LHRH-Ant) protected both male and female mice from BM failure, increased the recovery of myeloid and lymphoid compartments, and ultimately promoted overall mouse survival when administered 24 hours after lethal total body irradiation (LTBI). Underlying this, we could demonstrate both phenotypically and functionally that LHRH-Ant spared HSCs from radiation-induced depletion and induced HSCs into cell cycle, thereby promoting hematopoiesis. Intriguingly, use of an LHRH agonist, which causes an initial surge in sex steroids, also mediated enhanced survival from LTBI but surgical castration did not, suggesting that the benefit of SSI is not mediated by the sex steroids themselves but rather by upstream regulators such as LH. Consistent with this, irradiated mice receiving LHRH-Ant and treated daily with LH were no longer protected from radiation injury. Taken together these data not only reveal a novel mechanism that regulates HSC function, but also offer a therapeutic approach to regenerate hematopoiesis after radiation exposure.