Dkk1-Endothelial Progenitor Cell Treatment for the Mitigation of Hematopoietic Radiation Injury

项目摘要 该项目建议评估Dkk1处理的内皮祖细胞(Dkk1- 内皮祖细胞)通过促进伴随的血管和造血来减轻对骨髓的辐射损伤 恢复。这项工作的最终目标是开发一种可以在48小时后使用的细胞疗法 受伤以挽救因感染等造血毒性而遭受辐射照射死亡的受害者， 贫血和出血。这在临床上是有意义的，因为很可能有数十万受害者 如果发生大规模核恐怖袭击或放射性恐怖袭击，则具有急性造血毒性。大体上 在伤亡情况下，由于受害者人数众多，治疗可能会延误；然而，目前 标准护理Neupogen(G-CSF)只有在与前24名患者一起使用时才能证明对生存有好处 几个小时。因此，我们建议描述一种新的基于细胞的放射治疗的特征。 对骨髓的损伤。 我们实验室和其他实验室过去的工作表明，内皮细胞的输注可以加速 造血恢复和挽救受到致命性照射的小鼠，使其免于因造血综合征死亡。在这 建议，我们证明了Dkk1的预处理刺激内皮细胞产生再生和 血管生成因子，如表皮生长因子。此外，我们还证明了同种异体移植 Dkk1治疗的内皮祖细胞(Dkk1-EPC)显著促进5Gy后血管和造血的恢复 全身照射与生理盐水或EPC单独治疗相比。基于这些发现，我们假设 DKK1-EPC是一种潜在的细胞疗法，可减轻ARS患者的造血毒性。 为了验证这一假设，我们提出了以下具体目标：1)确定系统性给药 Dkk1-EPC可提高致死性照射小鼠的存活率。2)确定Dkk1-EPC是否减轻对 照射人骨髓CD34+细胞。3)开发人内皮祖细胞临床资源。4)确定蜂窝 Dkk1-EPC促进辐射小鼠再生的机制。

Project Summary 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.