Modulating Exosome Cargos and Surfaces for Precision Heart Repair

已经确定，移植细胞的大部分有益效果是间接的： 注射的细胞分泌促进内源性心脏修复的旁分泌因子。人中 分泌物质，外泌体是由多种细胞类型分泌的30-100 nm囊泡 包括肿瘤细胞和干细胞。外泌体可以转运微RNA（miR）， 细胞与相邻细胞通信以改变它们的行为。重要的miR货物 外来体的潜在治疗效力尚未确定。此外，与 干细胞、外来体不具有迁移能力，因此进行局部注射， 确保交付。然而，直接注射到心脏中并不是微不足道的，通常需要打开- 胸部手术或复杂的肌内膜注射设置，如NOGA标测 系统关键是开发将全身递送的外泌体靶向至肿瘤细胞的技术。 心脏损伤我们的长期目标是创造具有优化的货物和表面的外泌体， 精确的心脏修复在我们的初步研究中，我们比较了培养的心脏基质细胞， 从正常和衰竭的人类心脏中，并从这些细胞中分离出外泌体。体外 实验和动物研究表明，来自哺乳动物的外来体的再生活性受损， 心力衰竭患者。此外，miR阵列揭示了心力衰竭中miR-21的失调 外来体基于这些初步结果，我们假设：i）有一个损失， 在来自心力衰竭的外来体中的治疗性质，并且这种功能丧失是由于 i）改变所有库miR如miR-21; ii）调节此类miR货物可以挽救miR-21的表达。 患病外泌体的再生潜力; iii）有效的全身递送和损伤 靶向可以通过外泌体表面修饰来实现。本提案中提议的研究 是非常重要的，因为它们旨在加强我们对机制的基本理解， 潜在的外泌体的修复功能，但也可能为未来的临床 翻译.

It has been established that most of the beneficial effects of transplanted cells are indirect: injected cells secrete paracrine factors that promote endogenous heart repair. Among those secreted substances, exosomes are 30-100 nm vesicles secreted by a wide range of cell types including tumor cells and stem cells. Exosomes can transport microRNAs (miRs) that enable cells to communicate with neighboring cells to change their behavior. The essential miR cargos underlying the therapeutic potencies of exosomes have yet to be determined. In addition, unlike stem cells, exosomes do not have migratory ability therefore local injections are performed to ensure delivery. However, direction injection into the heart is not trivial, normally requiring open- chest surgery or sophisticated endomyocardial injection setups such as the NOGA mapping system. It is crucial to develop techniques to target systemically delivered exosomes to the heart injury. Our long-term goal is to create exosomes with optimized cargos and surfaces for precision cardiac repair. In our preliminary studies, we compared cultured cardiac stromal cells from normal and failing human hearts, and isolated exosomes from these cells. In vitro experiments and animal studies indicate an impaired regenerative activity of exosomes from heart failure patients. In addition, miR array revealed dysregulation of miR-21 in heart failure exosomes. Based on those preliminary results, we hypothesize that: i) there is a loss of therapeutic properties in exosomes from heart failure and such functional loss is due to alterations in repertoire miRs such as miR-21; ii) modulating such miR cargos could rescue the regenerative potential of the diseased exosomes; iii) efficient systemic delivery and injury targeting can be achieved by exosomal surface modification. Studies proposed in this proposal are highly significant since they aim to enhance our fundamental understating of mechanisms underlying exosomes' reparative function but may also pave the way for future clinical translation.