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

Dkk1-内皮祖细胞治疗减轻造血放射损伤

• 批准号: 10202467
• 负责人: Heather A Himburg
• 金额: $ 78.02万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-12 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202467
• 关键词: Acute; Address; Allogenic; Anemia; Angiogenic Factor; Animals; Area; Autologous; Blood Vessels; Bone Marrow; Bone Marrow Aspiration; CD34 gene; CSF3 gene; Cause of Death; Cell Line; Cell Therapy; Cells; Cessation of life; Clinical; Cryopreservation; Data; Dose; Endothelial Cells; Endothelium; Epidermal Growth Factor; Event; Exposure to; Failure; Filgrastim; Funding Opportunities; Goals; Growth Factor; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemorrhage; Homologous Transplantation; Hour; Human; Human Resources; In Vitro; Individual; Infection; Infusion procedures; Injury; Laboratories; Mediating; Modeling; Mus; National Institute of Allergy and Infectious Disease; Natural regeneration; Nuclear; Nuclear Accidents; Organ; PGF gene; Patients; Production; Radiation; Radiation Injuries; Radiation Toxicity; Radiation exposure; Radiology Specialty; Recovery; Research; Role; Safety; Saline; Source; Syndrome; System; Testing; Therapeutic; Time; Toxic effect; Transplantation; Umbilical Cord Blood; VEGFA gene; Whole-Body Irradiation; Work; Xenograft Model; base; cell bank; clinically relevant; cytokine; differential expression; efficacy testing; endothelial stem cell; experience; gastrointestinal; improved; in vitro Assay; in vivo; jagged1 protein; loss of function; mass casualty; mesenchymal stromal cell; metropolitan; neutrophil; novel; peripheral blood; pleiotrophin; progenitor; radiation mitigation; regenerative; standard of care; stem cell growth; stem cells; therapeutically effective

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.

项目总结