Targeted Delivery of iPS-Endothelial Cells for the Repair of Cardiovascular Injur

描述（由申请人提供）：在过去十年中，用于心血管疾病（CVD）的基于细胞的疗法已经激增，但成功有限。成功的细胞疗法的主要障碍是1）细胞类型选择（例如祖细胞与分化的），2）时间或细胞递送（例如急性与慢性），3）细胞递送模式（例如，外周相对于直接进入组织），4）移植细胞的排斥（例如，自体相对于异源），并且最重要的是，5）将细胞靶向递送至受损器官以使治疗效果最大化。我们已经开发了一种创新的策略，以克服这些障碍，静脉注射使用内皮细胞（EC）过度表达中性粒细胞白细胞介素-8（IL-8）受体到大鼠颈动脉腔内损伤或心肌梗死。本提案中概述的研究将这种靶向细胞递送策略扩展到更适用的干细胞类型，自体iPS-EC（诱导多能内皮干细胞）;以避免未来转化和/或临床研究中可能出现的细胞排斥问题，并增强组织修复的功效。我们将描述静脉内施用的过表达IL 8 RA和IL 8 RB的成体EC或iPS-EC在具有实验性血管或心脏损伤的大鼠中的保护作用的机制。我们假设过表达IL 8受体的成人EC或iPS-EC将模拟靶向并粘附于损伤组织（例如，损伤动脉的腔内表面和外膜）的中性粒细胞的行为，并且这样做将与中性粒细胞浸润竞争并抑制中性粒细胞浸润，并减弱随后的炎症反应以及对组织的结构和功能损伤。这项建议的目的是：1）过表达嗜中性白细胞介素-8（IL 8）受体基因的诱导多能内皮干细胞（iPS-EC）的产生2）为了检验iPS-EC或过表达嗜中性粒细胞IL 8受体的成人EC的靶向递送是靶向递送的假设，IL 8 RA和/或IL 8 RB促进腔内血管损伤后动脉的结构和功能恢复。3)为了测试靶向递送iPS-EC或过表达嗜中性粒细胞IL 8 RA和IL 8 RB的成人EC促进实验诱导的心肌梗死（MI）后左心室（LV）的结构和功能恢复的假设。的结果 所提出的研究是重要的，因为它们有望为心血管损伤的治疗干预提供创新策略。此外，预期该结果将通过提供非侵入性和成本有效的治疗方式从根本上推进基于细胞的治疗领域。

DESCRIPTION (provided by applicant): Cell-based therapies for cardiovascular diseases (CVD) have proliferated over the past decade, but with limited success. The major hurdles for successful cell therapies are 1) cell type selection (e.g. progenitor vs. differentiated), 2) time or cell delivery (e.g. acute vs. chronic), 3) cell delivery mode (e.g. peripheral vs. directly into tissue), 4) rejection of transplanted cells (e.g. autologous vs. heterologous), and most importantly, 5) targeting delivery of cells to damaged organs to maximize therapeutic effects. We have developed an innovative strategy to overcome these hurdles by i.v. transfusing endothelial cells (ECs) overexpressing neutrophil interleukin-8 (IL8) receptors into rats with endoluminal injury of the carotid artery or myocardial infarction. Studies outlined in this proposa will extend this targeted cell delivery strategy to a more applicable stem cell type, autologous iPS-ECs (induced pluripotent endothelial stem cells); to avoid possible cell rejection problems in future translational and/or clinical studies and enhances the efficacy of tissue repair. We will delineate the mechanism(s) of the protective effects of i.v. administered adult ECs or iPS-ECs overexpressing IL8RA and IL8RB in rats with experimental vascular or cardiac injury. We hypothesize that adult ECs or iPS-ECs that overexpress IL8 receptors will mimic the behavior of neutrophils that target and adhere to injured tissues (e.g. to endoluminal surface and adventitia of injured arteries) and in doing so will compete with and inhibit neutrophil infiltration and attenuate subsequent inflammatory responses and structural and functional damage to tissues. The Aims of this proposal are: 1) Generation of induced pluripotent endothelial stem cells (iPS-ECs) that overexpress neutrophil interleukin-8 (IL8) receptor genes (IL8RA and IL8RB) for targeted cell delivery to injured vascular and cardiac tissues.2) To test the hypothesis that targeted delivery of iPS-ECs or adult ECs overexpressing neutrophil IL8 receptors (IL8RA and/or IL8RB) promotes structural and functional recovery of arteries following endoluminal vascular injury. 3) To test the hypothesis that targeted delivery of iPS-ECs or adult ECs overexpressing neutrophil IL8RA and IL8RB promotes structural and functional recovery of the left ventricle (LV) following experimentally induced myocardial infarction (MI). The results of the proposed studies are significant because they are expected to provide an innovative strategy for therapeutic interventions for cardiovascular injury. In addition, it is expected that the results wll fundamentally advance the field of cell-based therapy by providing a noninvasive and cost effective treatment modality.