Exosomes as mediators of cardiac injury and repair

摘要 心肌具有固有的细胞替代能力，但这种修复过程是 不足以应对急性损伤或慢性应激时的大量细胞死亡。经收养转移 干细胞群体在临床试验中显示出希望，但捐赠细胞产生新细胞的功效 心肌或心肌功能的持续增加，仍然不大。极低的保留率和存活率 自体干细胞移植与自体干细胞功能活性降低的关系 既有疾病和糖尿病等共病因素可能解释了干细胞疗法有限的成功。 损伤的心肌和细胞外环境产生的分子信号很可能不是 有利于干细胞的存活、分化、迁移和整合。干细胞为基础的这些限制 治疗需要其他策略来提高基于细胞的治疗的效率。干细胞来源的- 外切体提供了一种替代的无细胞治疗方式。新的、非传统的无细胞使用 干细胞的组成部分，如外体，它们装载有亲本干细胞特有的MIR和蛋白质 可能允许利用这些细胞的再生能力，而不需要干细胞存活和 分化，增强和调节缺血的内源性保护和修复过程 心肌。因此，PPG中提出的研究提出了一个新的概念，并集中和深入 在这两个小的背景下对外切体的生物学特征、信号和功能的研究 和大型动物的心肌修复。项目1(Kishore)研究了炎症和压力等压力的作用。 糖尿病对骨髓内皮祖细胞外切体功能特性的影响 以及其他干细胞。项目2(沃尔特·科赫)专注于肾上腺素能受体和G-受体的参与。 心脏前体细胞衍生的外切体上的蛋白偶联蛋白激酶。项目3(Houser)关注的是 皮质骨干细胞外切体的特性和功能。所有三个项目都涉及深入的分子和 生理学研究包括心肌梗死的小动物模型和大动物模型。建立 基于干细胞的治疗的替代来源，如外切体，可能会克服直接治疗的障碍 细胞替代导致功能心肌和改善血流动力学性能。并发 促进愈合的强化疗法可以从改进的内源性功能修复中受益， 从而更有效地补偿心脏对病理性应激的反应。该计划中的项目将 证明外切体是干细胞功能和功能障碍的重要媒介，分子 外切体修复能力丧失的机制及改善其功能的途径 通过直接修饰识别的分子，如蛋白质和特定的microRNA，产生非 有效的心肌修复的许可条件。这个项目的目标将是描绘外显体 介导的信号机制并确定如何利用它们来恢复和增强内源 修复受损心脏的细胞修复过程。

Summary The myocardium possesses an inherent capacity for cellular replacement, yet this reparative process is inadequate to cope with the massive cell death during acute injury or chronic stress. Adoptively transferred stem cell populations showed promise in clinical trials but the efficacy of donated cells to generate new myocardium or lasting gain in myocardial function, remains modest. Extremely low retention and survival of transplanted stem cells and decreased functional activity of autologous stem cells from patients with established disease and co-morbid factors like diabetes may explain limited success with stem cell therapies. It is likely that the molecular signals produced by injured myocardium and extracellular environment are not favorable for stem cell survival, differentiation, migration, and integration. These limitations of stem cell-based therapies warrant alternate strategies to enhance efficiency of cell based therapies. Stem cell-derived- exosomes provide one such alternate cell-free therapeutic modality. Novel, non-traditional use of cell-free components of stem cells such as exosomes, which are loaded with parent stem cell-specific miRs and proteins may allow for harnessing the regenerative power of these cells, without the burden of stem cell viability and differentiation, to augment and modulate endogenous protection and repair processes in the ischemic myocardium. Studies proposed in this PPG therefore put-forth a novel concept and focused and in-depth investigation into the biology of exosome characterization, signaling and function in the context of both small and large animal myocardial repair. Project 1 (Kishore) examines the role of stresses like inflammation and diabetes on the functional properties of exosomes isolated from bone marrow endothelial progenitor cells as well as other stem cells. Project 2 (Walter Koch) focuses upon the involvement of adrenergic receptors and G- protein coupled kinases on cardiac progenitor cell-derived exosomes. Project 3 (Houser) is concerned with Cortical bone stem cell exosome characterization and function. All 3 projects involve in-depth molecular and physiological studies comprising of small and large animal models of myocardial infarction. Establishing alternate sources of stem cell based therapies, such as exosomes, may overcome the impediments to direct cellular replacement leading to functional myocardium and improved hemodynamic performance. Concurrent enhancement therapies to potentiate healing can then benefit from improved endogenous functional repair, leading to more effective compensation of the heart to pathologic stress. Projects in this program will demonstrate exosomes as the significant mediator of both stem cell function and dysfunction, molecular mechanisms responsible for loss of reparative capacity of exosomes and means to improve their functional capacity by directly modifying identified molecules such as proteins and specific microRNAs that create non- permissive conditions for efficient myocardial repair. The goal of this program will be to delineate exosome mediated signaling mechanisms and determine how they can be utilized to restore and enhance endogenous cellular repair processes that heal the damaged heart.