Pluripotent cell-derived exosomes as mediators of myocardial regeneration

描述（由申请人提供）：来自临床前和临床研究的现有证据表明，成人自体干细胞为基础的治疗显示出心脏功能的适度改善。来自临床前研究的新证据还表明，梗死心肌中的不良微环境，包括炎症和氧化损伤，对移植干细胞的存活和功能有不利影响，从而对基于成体干细胞的损伤心肌修复疗法构成重大障碍。因此，迫切需要新的方法来增强基于干细胞的治疗的全部功能益处。包括诱导多能干细胞（iPS）和胚胎干细胞（ESCs）在内的多能干细胞为受损心肌的再生提供了一种替代方法，但它们的使用在技术上仍然具有挑战性和风险，多能细胞的细胞衍生物可能仍然面临与成体干细胞类似的低植入和存活率的挑战。因此，使用来自干细胞（包括iPS和ES细胞）的无细胞成分，需要探索其修复潜力。来自这些细胞的外泌体可以提供一种这样的无细胞来源。外泌体是细胞间通讯的调节因子，携带细胞特异性mRNA/miRNA信号，并通过将其物质转移到靶细胞参与细胞间通讯。我们的初步数据表明，ESC衍生的外泌体代表了一种新的无细胞系统，能够通过诱导心肌细胞增殖和增强心脏祖细胞增殖、增殖和分化来支持心肌再生。因此，我们假设ES/ ips衍生的外泌体可能代表了一种增强梗死心肌内源性修复过程的新策略。我们的目标是建立多能干细胞衍生的外泌体作为一种新的无细胞治疗方案，用于慢性病理性损伤的心肌修复。这项研究的意义在于对mES细胞衍生的外泌体在支持心肌细胞和心脏祖细胞（CPCs）的心脏修复过程中所起的作用有了新的认识。我们还将扩展这些研究，以确定多能细胞特异性mirna在调节CPC对病理性损伤的修复反应中的作用。确定这些外泌体的治疗价值将有助于开发一种新的无细胞系统来增强心肌修复，并为内源性心肌修复过程的恢复和/或增强提供新的方向。

DESCRIPTION (provided by applicant): Available evidence from pre-clinical and clinical studies indicates that adult autologous stem cell based therapies show modest improvement of cardiac function. Emerging evidence from preclinical studies also suggests that hostile micro-environment in the infarcted myocardium, including inflammation and oxidative damage, have adverse effects on transplanted stem cell survival and function thereby posing a significant barrier to the adult stem cell-based therapies for repair of injured myocardium. Therefore, novel approaches to enhance full functional benefits of stem cell based therapies are critically needed. Pluripotent Stem cells including induced pluripotent stem cells (iPS) and embryonic stem cells (ESCs) have provided an alternative for the resurrection of damaged myocardium yet their use remains technically challenging and risky and cellular derivatives of pluripotent cells may still face the similar challenges of low engraftment and survival as is noted with adult stem cells. Therefore use of cell-free components derived from stem cells including iPS and ES cells, need to be explored for their reparative potential. Exosomes derived from such cells may provide one such cell-free source. Exosomes, known regulators of intercellular communication, carry the cell specific mRNA/miRNA signature and participate in cell-cell communication by transferring their materials to the target cells. Our preliminary data indicates that, ESC derived exosomes represent a novel cell free system capable of supporting myocardial regeneration, in part, by inducing cardiomyocyte proliferation and by enhancing cardiac progenitor cell augmentation, proliferation and differentiation. Therefore we hypothesize that ES/iPS-derived exosomes may represent a novel strategy to augment endogenous repair processes in the infarcted myocardium. Our goal is to establish that pluripotent stem cell-derived exosomes as a novel cell free therapeutic regimen for myocardial repair in response to chronic pathological insult. The significance of this study is to develop a novel understanding of the role played by mES cell derived exosomes in supporting cardiomyocyte and cardiac progenitor cells (CPCs) based reparative processes in the heart. We will also extend these studies to determine the contribution of pluripotent cell specific miRNAs in regulating CPC reparative response to pathologic injury. Establishing the therapeutic value of these exosomes would help develop a novel cell free system to enhance myocardial repair and would provide a new direction for the restoration and/or augmentation of endogenous myocardial repair process.