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: 9980461
• 负责人: Raj Kishore
• 金额: $ 228.81万
• 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/9980461
• 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; Coupled; Diabetes Mellitus; Disease; Environment; Exposure to; Financial compensation; Functional disorder; G protein coupled receptor kinase; GTP-Binding Proteins; Goals; Heart; Heart Diseases; Heart Injuries; Individual; Inflammation; Injury; Investigation; Mediating; Mediator of activation protein; MicroRNAs; Modality; 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; Stress; Techniques; Testing; Therapeutic; Therapeutic Agents; cardiac regeneration; cardiac repair; comorbidity; cortical bone; design; efficacy clinical trial; endothelial stem cell; exosome; extracellular; healing; heart cell; heart damage; hemodynamics; improved; injured; injury and repair; migration; myocardial injury; novel; programs; receptor; regenerative; repaired; stem cell model; stem cell population; stem cell therapy; stem cells; 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.

概括 心肌具有固有的细胞置换能力，但这种恢复过程是 不足以应对急性损伤或慢性应激期间的大规模细胞死亡。收养 干细胞种群在临床试验中显示出希望，但是捐赠细胞的功效产生了新的 心肌或心肌功能的持久增益仍然适中。保留和生存极低 移植的干细胞和来自患者的自体干细胞的功能活性降低 已建立的疾病和合并症等因素（如糖尿病）可以解释干细胞疗法的成功有限。 受伤的心肌和细胞外环境产生的分子信号可能不是 有利于干细胞存活，分化，迁移和整合。这些基于干细胞的局限性 疗法需要采取其他策略来提高基于细胞的疗法的效率。干细胞衍生的 外泌体提供一种这种替代的无细胞治疗方式。新颖的，非传统的无细胞使用 干细胞的成分，例如外泌体，这些成分装有母体干细胞特异性miR和蛋白质 可能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，增强和调节缺血性的内源性保护和修复过程 心肌。因此，该ppg提出的研究使得forth成为一个新颖的概念，并重点介绍 在两个小的背景下，研究外泌体特征，信号传导和功能的生物学 和大动物心肌修复。项目1（Kishore）研究了炎症和炎症等压力的作用 从骨髓内皮祖细胞中分离出的外泌体功能特性上的糖尿病 以及其他干细胞。项目2（Walter Koch）着重于肾上腺素能受体和G-的参与 蛋白质偶联的激酶在心脏祖细胞衍生的外泌体上。项目3（Houser）与 皮质骨干细胞外泌体特征和功能。所有3个项目都涉及深入分子和 由大小动物模型的心肌梗死模型组成的生理研究。建立 基于干细胞疗法的替代来源，例如外泌体，可能会克服障碍 细胞置换，导致功能性心肌并改善血液动力学性能。并发 然后，增强疗法的增强疗法可能会受益于改进的内源性功能修复， 导致心脏更有效地弥补病理压力。该程序中的项目将 将外泌体证明是干细胞功能和功能障碍的显着介体，分子 负责损失外泌体能力的机制和提高其功能的手段 通过直接修改已鉴定的分子（例如蛋白质和特定的microRNA）的能力，这些分子会产生非 - 有效的心肌修复的允许条件。该程序的目的是描述外泌体 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。