Therapeutic Mechanisms of Human CD34 Exosomes

人CD34外泌体的治疗机制

• 批准号: 9265122
• 负责人: Susmita Sahoo
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265122
• 关键词: Address; Binding; Biology; Blood Vessels; CD34 gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Cell Cycle Regulation; Cell Therapy; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Chronically Ill; Communication; Data; Discipline; Endothelial Cells; Foundations; Genetic Techniques; Goals; Growth; Heart; Human; Hypoxia; Injury; Laboratories; Lead; Mediating; Membrane; Membrane Proteins; MicroRNAs; Molecular; Molecular Biology Techniques; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Patients; Positioning Attribute; Process; Publishing; Recovery; Recovery of Function; Regenerative Medicine; Research; Research Personnel; Resistance; Signal Pathway; Signal Transduction; Stem Cell Research; Stem cell transplant; Stem cells; Surface; Testing; Therapeutic; Transplantation; Treatment Effectiveness; Treatment Efficacy; Vesicle; angiogenesis; base; cardiac angiogenesis; cardiac regeneration; cardiac repair; cell type; cellular targeting; effective therapy; exosome; experimental study; functional disability; human stem cells; improved; individualized medicine; innovation; insight; intercellular communication; laboratory experiment; mouse model; nanovesicle; novel; novel therapeutic intervention; paracrine; public health relevance; regenerative; repaired; stem cell therapy; success; trafficking; uptake

DESCRIPTION (provided by applicant): Stem cell-based therapies, including the recent CD34+ cell therapy, are a promising therapeutic approach for improving cardiac regeneration and function. The benefits of CD34+ cell transplantation appear to occur primarily via increase in vascular angiogenesis by the CD34+ cell-secreted paracrine factors in the ischemic myocardium. However, the precise mechanisms that lead to CD34+ cell-induced vessel growth and therapeutic recovery are poorly understood. This lack of mechanistic insight is a critical barrier to the success of cardiac stem cell therapy, as the regenerative efficacy of the transplanted stem cells is limited by their poor viability and retention in the ischemic myocardium. Therefore, to address these limitations and to develop novel alternate approaches, we must seek to understand the mechanisms that lead to therapeutic recovery. Our previously published data and our preliminary data have revealed that the paracrine secretion from human CD34+ cells contain membrane-bound nano-vesicles called exosomes (i.e. CD34+ exosomes), which are angiogenic and therapeutic similar to the cells. Further, CD34+ exosomes carry and transfer proangiogenic miRNAs, such as miR-126, to ischemic endothelial cells in the myocardium and induce their angiogenic activity. The fundamental basis of our proposal is to harness the regenerative potential and communication power of CD34+ exosomes to augment therapeutic approaches. Our central hypothesis is that exosomes released via paracrine secretion of human CD34+ cells mediate myocardial repair by direct transfer of miRNAs to cells in the heart. Our goal is to establish CD34+ stem cell-derived exosomes as a novel cell-free therapeutic entity for ischemic myocardial repair and to develop a comprehensive understanding of the molecular mechanisms of exosomes-induced cardiac angiogenesis and therapeutic recovery. This innovative study is important to understand the mechanisms of CD34+ cell therapy and to unlock the transformative potential of progenitor cell-derived exosomes. We will test our hypothesis in three specific aims: 1) Determine the therapeutic efficacy of cell-free CD34+ exosomes in a murine model of myocardial ischemia and determine whether CD34+ exosomes secretion is one of the key mechanisms of CD34+ cell therapy; 2) Characterize the molecular mechanisms of CD34+ exosomes-induced angiogenesis by studying the CD34+ exosomes trafficking and signaling mechanisms in the ischemic heart; 3) Establish the extent to which the beneficial effects of CD34+ exosomes are mediated by miR-126 in a murine model of MI. The experiments described in this proposal will explore key scientific questions by characterizing the predominant, but as yet undefined, mechanism of CD34+ stem cell therapy. Our studies will lay foundation to a novel therapeutic approach by using exosomes from human stem cells as a suitable cell-free alternative. It has the potential to advance cell- based therapis by exploiting many practical and technical advantages of exosomes relative to cells for application in cardiovascular regenerative medicine.

描述（由申请人提供）：基于干细胞的疗法，包括最近的CD34+细胞疗法，是改善心脏再生和功能的有希望的治疗方法。 CD34+细胞移植的益处似乎主要是通过缺血性心肌中CD34+细胞分泌的旁分泌因子增加血管血管生成。然而，对导致CD34+细胞引起的血管生长和治疗恢复的确切机制知之甚少。缺乏机械洞察力是对心脏干细胞疗法成功的关键障碍，因为移植的干细胞的再生功效受到其缺血性心肌的生存能力和保留率的限制。因此，要解决这些局限性并开发新的替代方法，我们必须寻求了解导致治疗恢复的机制。我们先前发表的数据和初步数据表明，人类CD34+细胞的旁分泌分泌包含膜结合的纳米虫，称为外泌体（即CD34+外泌体），它们是类似于细胞的血管生成和治疗性的。此外，CD34+外泌体携带和转移促进血管生成的miRNA，例如miR-126，转移到心肌中的缺血性内皮细胞中，并诱导其血管生成活性。我们建议的基本基础是利用CD34+外泌体的再生潜力和交流能力来增强治疗方法。我们的中心假设是，通过人类CD34+细胞的旁分泌分泌释放的外泌体通过将miRNA直接转移到心脏中的细胞中介导心肌修复。我们的目标是将CD34+干细胞衍生的外泌体建立为缺血性心肌修复的一种新型的无细胞治疗实体，并对外泌体诱导的心脏血管生成和治疗性恢复的分子机制有全面的理解。这项创新的研究对于了解CD34+细胞疗法的机制以及释放祖细胞衍生的外泌体的转化潜力很重要。我们将在三个特定目的中检验我们的假设：1）在心肌缺血的鼠模型中确定无细胞CD34+外泌体的治疗功效，并确定CD34+外泌体分泌是否是CD34+细胞治疗的关键机制之一； 2）通过研究缺血性心脏中的CD34+外泌体运输和信号传导机制来表征CD34+外泌体诱导的血管生成的分子机制； 3）确定在MI的鼠模型中miR-126介导CD34+外泌体的有益作用的程度。本提案中描述的实验将通过表征主要但尚未定义的CD34+干细胞疗法的机制来探讨关键科学问题。我们的研究将通过使用人类干细胞的外泌体作为一种合适的无细胞替代方案来为一种新型的治疗方法奠定基础。它具有通过利用外泌体相对于细胞在心血管再生医学中应用的许多实用和技术优势来推动基于细胞的治疗的潜力。