Harnessing Platelet-Endothelial Interactions for Stem Cell Delivery

项目总结 血小板-内皮相互作用在动脉粥样硬化和缺血性损伤等疾病中起着至关重要的作用 心肌梗死。心肌梗死后血管损伤/炎症可导致血小板活化和运输，上调 黏附分子的调节，以及血管中活性氧和氮物种的产生。 尽管在许多情况下，激活血小板是有害的，但最近的研究表明，缺血损伤后循环 干细胞(从骨髓中释放)依靠血小板进入受损心脏进行组织修复。 心肌梗死患者的血小板与循环干细胞形成共聚集体，从而 增加缺血微循环区域内的外周募集，促进与血管的黏附 血管损伤，促进愈合。在过去的十年里，我们一直在干细胞治疗领域工作 用于受伤后的心脏修复。一大挑战是将注入的干细胞靶向心脏损伤部位。穷 干细胞在心脏中的植入至少可以部分解释干细胞疗法的无边际疗效 到目前为止治疗心脏病的药物。我们假设干细胞上的血小板结合模体的表达可以帮助 他们的目标是受伤的心脏。我们设计了一种在干细胞上添加血小板结合基序的方法，而不需要 从基因上改变细胞。相反，瞬时表达可以通过细胞融合机制实现。我们会 首先从活的血小板产生血小板膜小泡，然后将这些小泡装饰到表面 治疗性干细胞。该方法具有较强的鲁棒性和简便性。在这项赠款研究的支持下，我们的目标是 评估这种方法对干细胞功能的细胞毒性，并测试这种方法的安全性/有效性 加强心肌梗死动物模型的内源性和外源性干细胞治疗。

PROJECT SUMMARY Platelet-endothelial interactions play a vital role in diseases such atherosclerosis and ischemic injury such as myocardial infarction. Vascular injury/inflammation after MI can lead to platelet activation and trafficking, up- regulations of adhesion molecules, and production of reactive oxygen and nitrogen species in vasculatures. Despite in many cases platelet activation is harmful, recent studies indicate that after ischemic injury circulating stem cells (release from the bone marrow) rely on platelets to navigate into the injured heart for tissue repair. Platelets form co-aggregates with circulating stem cells in patients with myocardial infarction and thereby increase peripheral recruitment within the ischemic microcirculatory district and promote adhesion to the vascular lesion to promote healing. For the last decade, we have been working in the field of stem cell therapy for post-injury cardiac repair. One big challenge is to target infused stem cells to the cardiac injury site. Poor cell engraftment in the heart may at least partially explain the none-to-marginal efficacy of stem cell therapies for heart diseases so far. We hypothesize that expression of platelet binding motifs on stem cells can help them target to the injured heart. We devised a method of adding platelet binding motifs onto stem cells without genetically altering the cells. Instead, transient expression can be achieved by cell fusion mechanisms. We will first generate platelet membrane vesicles from live platelets and then decorate these vesicles onto the surface of therapeutic stem cells. This method is robust and simple. Under the auspice of this grant study, we aim to evaluate the cytotoxicity of this approach on stem cell functions and test the safety/efficacy of this approach to enhance endogenous and exogenous stem cell therapies in animal models of myocardium infarction.