Exosomes as mediators of cardiac injury and repair

外泌体作为心脏损伤和修复的介质

• 批准号: 9357849
• 负责人: Raj Kishore
• 金额: $ 236.33万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357849
• 关键词: Activities of Daily Living; Acute; Adoptive Transfer; Adrenergic Agents; Adrenergic Receptor; Animal Model; Animals; Autologous; Biochemical; Biology; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Communication; Cell Culture Techniques; Cell Death; Cell Differentiation process; Cell Survival; Cell Therapy; Cell physiology; Cells; Chronic stress; Clinical; Clinical Research; Clinical Trials; Coupled; Diabetes Mellitus; Disease; Environment; Financial compensation; Functional disorder; G protein coupled receptor kinase; G-substrate; GTP-Binding Proteins; Goals; Heart; Heart Diseases; Heart Injuries; Individual; Inflammation; Injury; Investigation; Mediating; Mediator of activation protein; MicroRNAs; Modality; Modeling; Molecular; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Parents; Pathologic; Patients; Performance; Phenotype; Phosphotransferases; Physiological; Process; Property; Proteins; Regenerative Medicine; Regulation; Research Personnel; Role; Science; Scientist; Signal Transduction; Source; Stem cell transplant; Stem cells; Stress; Techniques; Testing; Therapeutic; Therapeutic Agents; cardiac regeneration; cardiac repair; cortical bone; design; efficacy trial; exosome; extracellular; healing; heart cell; hemodynamics; improved; injured; injury and repair; migration; novel; programs; receptor; regenerative; repaired; stem cell population; stem cell therapy; success; synergism; tissue repair

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.

总结 心肌具有细胞替换的固有能力，但这种修复过程是不可预测的。 不足以科普急性损伤或慢性应激期间的大量细胞死亡。过继转移 干细胞群体在临床试验中显示出希望，但捐赠细胞产生新的 心肌或心肌功能的持续增加，仍然适度。极低的保留率和存活率 移植的干细胞和降低的功能活性的自体干细胞的患者 确定的疾病和并发症因素，如糖尿病，可以解释干细胞疗法的有限成功。 很可能损伤的心肌和细胞外环境产生的分子信号不是 有利于干细胞存活、分化、迁移和整合。这些基于干细胞的 治疗保证了增强基于细胞的治疗的效率的替代策略。干细胞- 外来体提供了一种这样的替代的无细胞治疗方式。无细胞的新的非传统用途 干细胞的组分，如外泌体，其装载有亲本干细胞特异性miR和蛋白质 可以允许利用这些细胞的再生能力，而没有干细胞活力的负担， 分化，以增强和调节缺血性脑损伤中的内源性保护和修复过程。 心肌因此，本PPG提出的研究提出了一个新的概念，并重点和深入 调查外泌体表征的生物学，信号传导和功能，在小的背景下， 和大型动物心肌修复。项目1（Kishore）研究了炎症等应激的作用， 糖尿病对从骨髓内皮祖细胞分离的外泌体的功能特性的影响， 以及其他干细胞。项目2（沃尔特科赫）的重点是肾上腺素能受体和G- 心脏祖细胞衍生的外泌体上的蛋白偶联激酶。项目3（Houser）涉及 皮质骨干细胞外泌体的特性和功能。所有3个项目都涉及深入的分子和 生理学研究包括心肌梗塞的小型和大型动物模型。建立 基于干细胞的疗法的替代来源，例如外来体，可以克服直接治疗的障碍。 细胞替代导致功能性心肌和改善的血液动力学性能。并发 增强愈合的增强疗法然后可以受益于改善的内源性功能修复， 导致心脏对病理性应激的更有效的补偿。该计划中的项目将 证明外泌体是干细胞功能和功能障碍的重要介质， 负责外泌体修复能力丧失的机制和改善其功能的方法 通过直接修饰识别的分子，如蛋白质和特定的microRNA， 为有效的心肌修复创造条件。这个项目的目标是描绘外泌体 介导的信号传导机制，并确定如何利用它们来恢复和增强内源性 细胞修复过程可以治愈受损的心脏。