CPC Excosomes for Cardiac Therapy

描述（由申请人提供）：心肌梗死后心肌的不良重构加速心力衰竭的进展。虽然细胞疗法受到了极大的热情，但仍有许多缺点阻碍了长期的功能改善。此外，这些细胞来自患病个体，免疫原性限制了大多数研究的自体治疗。最后，人们普遍认为细胞治疗的主要作用是由旁分泌效应物介导的，而不是细胞本身。我们已经分离出大鼠和人类心脏祖细胞，它们是心脏来源的，表达c-kit，不表达任何心脏源性谱系标记，但可以分化为所有心脏细胞类型。这些细胞基本上释放microRNA （miR）到细胞外空间。当缺氧条件下处理时，这些细胞增加外泌体内的心脏保护miRs。初步研究表明，这些缺氧外泌体促进了成纤维细胞内皮管的形成，并降低了成纤维细胞中纤维化基因的表达。因此，本研究的目的是研究这些外泌体在大鼠缺血-再灌注模型中的保护/再生能力。此外，通过大量儿童和成人患者样本，我们可以进行多变量分析，以检查影响各种体内机制的因素。影响因素包括患者的年龄、性别和缺氧环境。这些研究的完成将确定缺氧外泌体是否是一种有益的缺血再灌注损伤治疗方法，以及确定促成这些反应的潜在患者因素。

DESCRIPTION (provided by applicant): Adverse remodeling of the myocardium after myocardial infarction speeds progression to heart failure. While cell therapy has been met with great enthusiasm, there are numerous shortcomings that prevent long-term functional improvements. Moreover, these cells come from diseased individuals and immunogenicity limits most studies to autologous therapy. Finally, it is widely believed that the main effect of cell therapy is mediated by paracrine effectors and not the cells themselves. We have isolated rat and human cardiac progenitor cells that are cardiac-derived, express c-kit, do not express any markers of cardiogenic lineage, but can differentiate in to all cardiac cell types. These cells basally release microRNA (miR) in to the extracellular space. When treated with hypoxic conditions, these cells increase cardioprotective miRs within exosomes. Preliminary studies demonstrate that these hypoxic exosomes enhance endothelial cell tube formation and decrease fibrotic gene expression in fibroblasts. Therefore, the objective of this proposal is to examine the protective/regenerative capacity of these exosomes in rat models of ischemia-reperfusion. Additionally, with a large number of patient samples from children and adults, we can perform multivariate analysis to examine the factors that affect various in vivo mechanisms. Factors include patient age, gender, and exposure to hypoxic conditions. Completion of the proposed studies will determine whether hypoxic exosomes are a beneficial therapy for ischemia-reperfusion injury, as well as determine potential patient factors that contribute to these responses.