Pluripotent cell-derived exosomes as mediators of myocardial regeneration

描述（由申请人提供）：临床前和临床研究的现有证据表明，基于成人自体干细胞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也表明，梗死心肌中的不利微环境，包括炎症和氧化损伤，对移植的干细胞存活和功能具有不利影响，从而对用于修复损伤心肌的基于成体干细胞的疗法构成显著障碍。因此，迫切需要新的方法来增强基于干细胞的疗法的全部功能益处。多能干细胞包括诱导多能干细胞（iPS）和胚胎干细胞（ESC）已经为受损心肌的复活提供了替代方案，然而它们的使用仍然具有技术挑战性和风险，并且多能细胞的细胞衍生物仍然可能面临与成体干细胞类似的低植入和存活的挑战。因此，使用来自干细胞的无细胞组分，包括iPS和ES细胞，需要探索其修复潜力。来源于此类细胞的外来体可提供一种此类无细胞来源。外泌体是已知的细胞间通讯调节因子，携带细胞特异性mRNA/miRNA标签，并通过将其物质转移到靶细胞来参与细胞间通讯。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，其能够部分地通过诱导心肌细胞增殖和通过增强心脏祖细胞扩增、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来源的外泌体作为一种新型的无细胞治疗方案，用于慢性病理损伤的心肌修复。本研究的意义是对mES细胞衍生的外泌体在支持心脏中基于心肌细胞和心脏祖细胞（CPC）的修复过程中所起的作用进行新的理解。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对病理损伤的修复反应中的作用。建立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，并将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.