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，梗死心肌中恶劣的微环境，包括炎症和氧化损伤，对移植的干细胞存活和功能有不利影响，从而对成人干细胞修复受损心肌的治疗构成了显著的障碍。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复苏提供了另一种选择，但它们的使用仍然具有技术挑战性和风险，多潜能细胞的细胞衍生体仍可能面临与成人干细胞类似的低植入率和存活率的挑战。因此，使用来自干细胞的无细胞成分，包括iPS和ES细胞，需要探索它们的修复潜力。从这种细胞衍生的外切体可以提供一种这样的无细胞来源。胞外体是已知的细胞间通讯的调节者，携带细胞特有的mRNA/miRNA信号，通过将其物质转移到靶细胞来参与细胞间的通讯。我们的初步数据表明，ESC来源的外切体是一种新的无细胞系统，能够部分地通过诱导心肌细胞增殖和促进心脏前体细胞的扩增、增殖和分化来支持心肌再生。因此，我们假设ES/iPS来源的外切体可能代表了一种新的策略来增强梗死心肌的内源性修复过程。我们的目标是建立多能干细胞来源的外切体作为一种新的无细胞治疗方案，用于应对慢性病理性损伤的心肌修复。本研究的意义在于对MES细胞来源的外切体在支持心肌细胞和心脏前体细胞(CPC)修复过程中所起的作用有一个新的认识。我们还将扩大这些研究，以确定多能细胞特异性miRNAs在调节CPC对病理损伤的修复反应中的作用。确定这些外切体的治疗价值将有助于开发一种新的无细胞系统来加强心肌修复，并将为恢复和/或加强内源性心肌修复过程提供新的方向。

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.