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

项目摘要 本项目旨在评估Dkk 1处理的内皮祖细胞（Dkk 1 - 2000）的给药是否 EPCs）通过促进伴随的血管和造血功能来减轻骨髓的辐射损伤 复苏这项工作的最终目标是开发一种细胞疗法，可以在肿瘤发生后>48小时内施用。 为了抢救辐射暴露受害者免于因造血毒性（如感染）而死亡， 贫血和出血这与临床相关，因为可能有数十万受害者 如果发生大规模核或放射性恐怖袭击，会出现急性造血毒性。按质量 在伤亡情况下，由于受害者人数众多，治疗可能会延迟;然而，目前 标准治疗Neupogen（G-CSF）仅在前24小时给药时具有已证实的生存益处。 小时因此，我们提出了一种新的基于细胞的救援疗法，以减轻辐射 骨髓损伤。 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 造血恢复和挽救致死辐射小鼠免于因造血综合征而死亡。在这 我们的研究表明，用Dkk 1预处理可以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，我们表明，同种异体移植， Dkk 1处理的EPCs（Dkk 1-EPCs）在5戈伊照射后显著改善血管和造血恢复 全身照射与单独的盐水或EPC治疗相比。基于这些发现，我们假设 Dkk 1-EPCs是一种潜在的缓解ARS病毒造血毒性的细胞治疗剂。 为了验证这一假设，我们提出了以下具体目标：1）确定是否全身给药 Dkk 1-EPCs提高了致死辐射小鼠的存活率。2)确定Dkk 1-EPCs是否减轻了对 照射人BM CD 34+细胞。3)开发人类EPCs的临床资源。4)确定细胞 Dkk 1-EPCs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.