This project proposes to assess whether administration of Dkk1-treated endothelial progenitor cells (Dkk1- EPCs) mitigates radiation injury to the bone marrow by promoting concomitant vascular and hematopoietic recovery. The ultimate goal of this work is to develop a cell therapy that can be administered >48 hours after injury to rescue victims of radiation exposure from death due to hematopoietic toxicities such as infection, anemia, and hemorrhage. This is clinically relevant as there are likely to be several hundred thousand victims with acute hematopoietic toxicities if a large-scale nuclear or radiological terror attack were to occur. In a mass casualty scenario, treatment is likely to be delayed due to the large volume of victims; however, the current standard of care Neupogen (G-CSF) only has proven survival benefit when administered with the first 24 hours. Therefore, we propose to characterize a novel cell-based rescue therapy for mitigation of radiation injury to the bone marrow. Past work from our laboratory and others has shown that infusion of endothelial cells can accelerate hematopoietic recovery and rescue lethally irradiated mice from death due to hematopoietic syndrome. In this proposal, we show that pre-treatment with Dkk1 stimulates endothelial cells to produce regenerative and angiogenic factors such as epidermal growth factor. Furthermore, we show that allogeneic transplantation of Dkk1-treated EPCs (Dkk1-EPCs) significantly improved vascular and hematopoietic recovery following 5 Gy total body irradiation compared to saline or EPC treatment alone. Based on these findings, we hypothesize that Dkk1-EPCs are a potential cellular therapeutic for the mitigation of hematopoietic toxicities in ARS vicitims. To test this hypothesis, we propose the following specific aims: 1) Determine whether systemic administration of Dkk1-EPCs improves survival in lethally irradiated mice. 2) Determine whether Dkk1-EPCs mitigate injury to irradiate human BM CD34+ cells. 3) Develop a clinical resource of human EPCs. 4) Determine the cellular mechanisms through which Dkk1-EPCs promote regeneration in irradiated mice.
This application meets the goal of this NIAID funding opportunity as it proposes an effective cellular therapy for mitigation of hematologic radiation injury. Furthermore, it addresses an unmet clinical need for mitigators that can be delivered 24 hours or more post injury.
