Vascular niche restoration to prevent delayed effects of acute radiation exposure (DEARE) in the hematopoietic system

About This Grant

Project Summary For survivors of acute radiation sickness (ARS), the delayed effects of acute radiation exposure (DEARE) can affect multiple organs over time, leading to chronic degenerative diseases and increased risk of cancer. Perhaps no organ system is more profoundly at risk for life threatening DEARE than the hematopoietic system. Multiple longitudinal studies of the Hiroshima and Nagasaki atomic bombing survivors cohort have demonstrated that the highest radiation- induced cancer risk was for leukemia, which had the highest cancer frequency and impact on atomic bomb survivor mortality within the first 10 years after the bombings. Additional studies confirmed an increased incidence of myelodysplasia, a pre-leukemic state in the hematopoietic system, in survivors of the Nagasaki bombing, with elevated risk persisting for up to 60 years. Emergency cleanup workers from Chernobyl similarly suffered increased incidence of acute leukemia during the first 11 years after the accident. Animal studies have demonstrated that single gamma radiation exposures cause persistent DNA damage and apoptosis in long-term hematopoietic stem cells (LT HSCs) and depletion of HSCs capable of reconstituting hematopoiesis. We hypothesize that therapeutic restoration of the bone marrow (BM) vascular niche, wherein HSCs reside, after ARS will facilitate the regeneration of long-term HSCs and prevent ongoing radiation-induced damage to the hematopoietic compartment. Research over the past decade has confirmed that long-term HSCs depend upon paracrine signals from BM endothelial cells (BM ECs) and perivascular stromal cells for their maintenance and regeneration following radiation injury. Furthermore, BM ECs regulate the maintenance of HSC genomic integrity, HSC DNA repair and inflammatory mechanisms in the niche. We have discovered that inhibition of SEMA3A – Nrp1 signaling in BM ECs blocks radiation-induced BM EC apoptosis after ARS and accelerates restoration of the intact BM vascular niche in irradiated mice. In this project, we will test whether inhibition of Nrp1 signaling and early restoration of the healthy BM vascular niche can prevent the delayed adverse effects of radiation on the hematopoietic system: HSC depletion, BM failure, clonal hematopoiesis and leukemia. Our preliminary data suggest that Nrp1 inhibition markedly augments the early recovery of the most primitive SLAM KSL HSCs in irradiated mice, suggesting that this mechanism can mitigate radiation-induced HSC depletion following ARS. When combined with GCSF, Nrp1 inhibition has the potential to broaden our therapeutic horizon beyond ARS and to mitigate ominous delayed effects, including BM failure, myelodysplasia and leukemic transformation.