Endothelial cell transplantation for multi-organ repair to counter radiation injury

内皮细胞移植用于多器官修复以对抗辐射损伤

基本信息

批准号：
9904499
负责人：
HANS-PETER KIEM
金额：
$ 59.88万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-18 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904499
关键词：
Abnormal Endothelial Cell Acute Address Agonist Allogenic Animal Model Animals Blood Coagulation Disorders Blood Vessels Blood capillaries Bone Marrow Transplantation Cell Therapy Cell Transplantation Cell physiology Chronic Cicatrix Cirrhosis Clinic Clinical Clinical Engineering Cryopreservation Defect Destinations Drug Kinetics Edema Endothelial Cells Ensure Exposure to Failure Family suidae Fibrosis Freezing Functional disorder Future Genetic Goals Growth Factor Guidelines Hematopoietic Hematopoietic Stem Cell Transplantation Hemorrhage Home environment Human Immune Impairment Infection Inflammation Injury Instruction Intestines Intravenous Ionizing radiation Kinetics Lead Life Liver Lung Lymphatic Lymphatic Endothelial Cells Macaca nemestrina Marrow Measures Medical Methods Modeling Molecular Monkeys Mus Natural regeneration Neutropenia Organ Outcome Participant Pathogenesis Pharmacodynamics Preclinical Testing Procedures Quality of life Radiation Radiation Injuries Radiation Syndromes Radiation Tolerance Radiation Toxicity Radiation exposure Radiation induced damage Recovery Rodent Safety Schedule Sclerosis Secondary to Signal Transduction Syndrome Testing Therapeutic Therapeutic Uses Tissues Toxic effect Translating Transplantation Tumorigenicity Umbilical vein Vascular Graft Work angiogenesis cell bank cell injury experimental study gastrointestinal healing hematopoietic engraftment improved injury and repair irradiation liver function nonhuman primate operation organ injury paracrine preconditioning premature prevent radiation countermeasure regenerative repaired reproductive restoration safety testing secondary infection senescence success therapy development tumorigenesis vascular bed

项目摘要

Abstract Exposure to ionizing radiation is often fatal due to acute radiation syndromes (ARS) manifested as Gastrointestinal-ARS (GI-ARS) and Hematopoietic-ARS (H-ARS). Delayed effects of acute radiation exposure (DEARE) lead to multi-organ dysfunction syndrome (MODS). A common denominator of radiation induced multi-organ failure is due to damage to endothelial cells (ECs) and lymphatic ECs, resulting in leakiness, coagulopathy and inflammation, setting up stage for infection, sclerosis and tumorigenesis. The molecular basis of radiation-induced EC dysfunction is not well understood. Our goal is to capitalize on the regenerative function of ECs by intravenously transplanting readily-available, off-the- shelf, allogeneic human ECs to mitigate ARS, DEARE and MODS. Our central hypothesis is that radiation damaged blood vessel and lymphatic ECs become dysfunctional and fail to perform their vascular functions or supply the instructive signals required to promote tissue healing thereby leading to ARS and DEARE. We propose that transplantation of normal pro-regenerative ECs a day or days after radiation can rescue the multi-organ defects of radiation-injured ECs and promote scar-free healing. We have shown that tissue-specific ECs by producing angiocrine growth factors orchestrate the repair of injured organs without fibrosis. Intravenous transplantation of human ECs restores hematopoietic recovery in sublethally irradiated rodents and lethally irradiated pigtail macaque non-human primates (NHP) without fibrosis or tumorigenesis. The Rationale for the proposed experiments is that if we know how to efficiently generate abundant off-the-shelf GMP-grade human umbilical vein ECs (HUVECs) as a “generic allogeneic vascular graft”, we will use NHP large animal model radiation models to determine the pharmacokinetics of HUVEC transplantation to use them as a definitive or intermediary radiation countermeasure to support organ repair post-radiation. We will test this hypothesis by addressing these Aims: 1) Manufacture of abundant functional clinical-grade master cell banks of monkey ECs (MUVECs) and human (HUVECs) for intravenous transplantation. 2) Identify the critical parameters for allogeneic/xenogeneic MUVEC and HUVEC transplantation into recipient mice to mitigate post-irradiation H-ARS and GI-ARS injury without provoking fibrosis..3) Employ pigtail macaque NHP radiation models to determine the scheduling, safety and efficacy of transplanting MUVECs and HUVECs to rejuvenate vascular niche for multi-organ repair without scarring. Completion of the proposed studies will enable therapeutic use of allogeneic off-the-shelf “human ECs” that transiently home to the disrupted vascular beds of irradiated organs restoring angiogenesis and vascular niche functions promoting organ repair, scarring. The success of these studies will provide for a readily available medical counter measure (MCM) for the treatment of acute and chronic radiation syndromes preventing life threatening complications. 1

抽象的暴露于电离辐射通常是致命的，因为急性辐射综合症（ARS）表现为胃肠道-ARS (GI-ARS) 和造血-ARS (H-ARS) 急性辐射的延迟效应。暴露（DEARE）导致多器官功能障碍综合征（MODS）的一个共同点。辐射引起的多器官衰竭是由于内皮细胞（EC）和淋巴管 EC 受损所致，导致渗漏、凝血障碍和炎症，为感染、硬化和炎症奠定基础辐射引起的 EC 功能障碍的分子基础尚不清楚。是通过静脉内移植现成的、现成的来利用 EC 的再生功能货架、同种异体人类 EC 可以减轻 ARS、DEARE 和 MODS 我们的中心假设是辐射。受损的血管和淋巴管内皮细胞功能失调，无法发挥其血管功能功能或提供促进组织愈合所需的指导信号，从而导致 ARS 和 DEARE。我们建议在辐射后一天或几天移植正常的促再生 EC。我们已经证明，可以挽救放射损伤的 EC 的多器官缺陷并促进无疤痕愈合。组织特异性内皮细胞通过产生血管分泌生长因子来协调受损器官的修复人类ECs的静脉移植可在亚致死的情况下恢复造血功能。受辐射的啮齿动物和致命辐射的猪尾猴、非人灵长类动物（NHP），无纤维化或所提出的实验的基本原理是，如果我们知道如何有效地生成肿瘤。丰富的现成 GMP 级人脐静脉 EC（HUVEC）作为“通用同种异体血管移植”，我们将使用NHP大动物模型辐射模型来确定HUVEC的药代动力学移植，将它们用作支持器官的最终或中间辐射对策我们将通过解决以下目标来检验这一假设：1）制造丰富的猴 EC (MUVEC) 和人 (HUVEC) 的功能性临床级主细胞库 2) 确定同种异体/异种 MUVEC 的关键参数和将 HUVEC 移植到受体小鼠中以减轻照射后 H-ARS 和 GI-ARS 损伤，而无需引发纤维化..3) 采用猪尾猕猴 NHP 辐射模型来确定调度、安全性移植MUVECs和HUVECs以恢复血管生态位以进行多器官修复的效果和功效完成拟议的研究将使同种异体现成的治疗用途成为可能。 “人类内皮细胞”短暂地驻留在受辐射器官破坏的血管床中以恢复血管生成和血管生态位功能促进器官修复、疤痕形成这些研究的成功。将为治疗急性和慢性疾病提供现成的医疗对策（MCM）放射综合征可预防危及生命的并发症。 1