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

描述（由申请人提供）：在过去的十年中，基于细胞的心血管疾病（CVD）治疗激增，但成功有限。成功的细胞治疗的主要障碍是1)细胞类型选择（如祖细胞与分化细胞），2)时间或细胞递送（如急性与慢性），3)细胞递送模式（如外周与直接进入组织），4)移植细胞的排斥反应（如自体与异体），最重要的是，5)靶向递送细胞到受损器官以最大化治疗效果。我们已经开发了一种创新的策略，通过静脉输注过度表达中性白细胞介素-8 （IL8）受体的内皮细胞（ECs）到颈动脉腔内损伤或心肌梗死的大鼠中来克服这些障碍。本提案中概述的研究将把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-ECs（诱导多能内皮干细胞）；为了避免在未来的翻译和/或临床研究中可能出现的细胞排斥问题，并提高组织修复的功效。我们将描述静脉注射过表达IL8RA和IL8RB的成年ECs或iPS-ECs对实验性血管或心脏损伤大鼠的保护作用机制。我们假设，过度表达il - 8受体的成年ECs或iPS-ECs将模仿中性粒细胞的行为，这些中性粒细胞靶向并粘附在受损组织上（例如，损伤动脉的腔内表面和外膜），这样做将与中性粒细胞浸润竞争并抑制中性粒细胞浸润，减轻随后的炎症反应以及对组织的结构和功能损伤。本研究的目的是：1)生成诱导多能性内皮干细胞（iPS-ECs），该干细胞过度表达中性粒细胞白细胞介素-8 （IL8）受体基因（IL8RA和IL8RB），用于靶向细胞递送到损伤的血管和心脏组织。2)验证靶向递送iPS-ECs或过表达中性粒细胞il - 8受体（IL8RA和/或IL8RB）的成人ECs促进腔内血管损伤后动脉结构和功能恢复的假设。3)验证靶向递送iPS-ECs或过表达中性粒细胞IL8RA和IL8RB的成人ECs促进实验性心肌梗死（MI）后左心室（LV）结构和功能恢复的假设。研究的结果

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.