Hematopoietic failure is the major cause of death in Acute Radiation Sickness. Unfortunately, few therapies exist that are effective at mitigating radiation-induced damage to the hematopoietic system. We hypothesized that cells within the bone marrow microenvironment, specifically endothelial cells (ECs), regulate hematopoietic regeneration following radiation injury. As a means to test this hypothesis, we generated mice bearing deletion of the intrinsic mediators of apoptosis, Bak and Bax, within Tie2+ endothelial cells (Tie2Cre;Bak-/-;BaxFl/- mice) and found that mice with deletion of Bak and Bax in Tie2+ ECs were radioprotected from lethal dose irradiation, whereas mice retaining 1 allele of Bax in Tie2+ ECs remained highly radiosensitive. We performed a cytokine array analysis of bone marrow serum from radioprotected Tie2Cre;Bak-/-;BaxFl/- mice and identified several secreted proteins which were significantly upregulated in radioprotected mice compared to radiosensitive mice. One protein identified was epidermal growth factor (EGF), which is not known to be a growth factor for hematopoietic stem cells (HSCs), but was 18-fold increased in concentration in the BM serum of radioprotected mice compared to control mice. We therefore tested in preliminary studies whether the addition of EGF to cultures of irradiated murine BM HSCs caused the mitigation of radiation injury to HSCs or progenitor cells. Our preliminary results indicate that EGF promotes a significant increase in the recovery of HSCs and progenitor cells in vitro following irradiation. Furthermore, we found that systemic administration of EGF to mice following total body irradiation (TBI) caused a significant increase in mice survival compared to irradiated, control mice. Based on these preliminary results, we hypothesize that EGF is a candidate mitigator of acute radiation sickness and specifically the hematopoietic failure which ensues following acute radiation injury. In order to test our hypothesis, we propose the following Specific Aims: 1) Determine whether systemic administration of EGF can accelerate hematopoietic recovery and improve the survival of mice following radiation injury. 2) Determine the cellular and signaling mechanisms through which EGF mitigates radiation damage to hematopoietic stem cells. 3) Determine whether EGF treatment can improve hematopoietic recovery in rhesus macaques following total body irradiation. Our broad objective in this proposal is to deliver a novel, translatable and potent mitigator of radiation-induced hematopoietic injury. In addition to its potential role as a mitigator of acute radiation injury, EF also has potential dual use as a therapeutic to accelerate hematopoietic recovery in patients receiving myelosuppressive chemotherapy and/or radiotherapy and those undergoing human cord blood transplantation, in which hematologic recovery is frequently delayed.
This project will meet the public health goals of the NIAID by testing and developing an entirely new treatment for radiation injury. The development of effective treatments for radiation injury to the blood and immune systems is a principle goal for the NIAID and this project will take a new and exciting approach to meeting this objective.
|Himburg, Heather A; Doan, Phuong L; Quarmyne, Mamle et al. (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91-99|
|Himburg, Heather A; Sasine, Joshua; Yan, Xiao et al. (2016) A Molecular Profile of the Endothelial Cell Response to Ionizing Radiation. Radiat Res 186:141-52|
|Yan, Xiao; Himburg, Heather A; Pohl, Katherine et al. (2016) Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration. Cell Rep 17:1584-1594|