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

描述(申请人提供)：基于细胞的治疗心血管疾病(CVD)在过去十年中激增，但成效有限。成功的细胞治疗的主要障碍是1)细胞类型的选择(例如，祖细胞和分化细胞)，2)时间或细胞输送(例如，急性和慢性)，3)细胞输送方式(例如，外周和直接进入组织)，4)移植细胞的排斥反应(例如，自体和异体)，以及最重要的是，5)靶向将细胞输送到受损的器官以最大限度地发挥治疗效果。我们开发了一种创新的战略，通过静脉注射克服这些障碍。将高表达中性粒细胞白介素8(IL8)受体的内皮细胞(ECs)输注到颈动脉腔内损伤或心肌梗死大鼠体内。这项提议中概述的研究将把这种靶向细胞输送策略扩展到一种更适用的干细胞类型--自体iPS-ECs(诱导多能内皮干细胞)；以避免未来翻译和/或临床研究中可能出现的细胞排斥问题，并提高组织修复的效率。我们将描述静脉注射保护作用的机制(S)。对实验性血管或心脏损伤大鼠给予高表达IL8RA和IL8RB的成体内皮细胞或iPS-ECs。我们假设，过表达IL8受体的成人内皮细胞或iPS-ECs将模仿中性粒细胞的行为，靶向并附着于损伤组织(例如，损伤动脉的管腔内表面和外膜)，这样做将与中性粒细胞竞争并抑制中性粒细胞的渗透，减轻随后的炎症反应和对组织的结构和功能损伤。该建议的目的是：1)建立高表达中性粒细胞白介素8受体基因(IL8RA和IL8RB)的诱导多能内皮干细胞(iPS-ECs)，用于靶向细胞输送至受损的血管和心脏组织。2)验证靶向输送iPS-ECs或高表达中性粒细胞IL8受体的成年内皮细胞(IL8RA和/或IL8RB)促进血管内膜损伤后动脉结构和功能恢复的假说。3)验证靶向输送iPS-ECs或高表达中性粒细胞IL8RA和IL8RB的成年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说。评选结果 拟议的研究具有重要意义，因为它们有望为心血管损伤的治疗干预提供一种创新的策略。此外，预计这些结果将通过提供一种非侵入性和成本效益高的治疗方式，从根本上推动基于细胞的治疗领域的发展。

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.