Cardioprotective Repair through Cardiopoiesis

心肌梗塞是导致收缩性能丧失的主要原因 由于心肌的自我更新能力有限。胚胎干细胞的能力 分化为心肌细胞提供了再生修复的机会。确实，基础 这些典型干细胞的治疗用途在于其固有的多能性，但其独特的 多谱系分化的能力带来的肿瘤生长的责任超过了益处 阻碍修复性应用。该提案的目的是磨练干细胞的可塑性，以便 消除易于发生恶性肿瘤的无引导分化以进行安全修复。初步研究表明 胚胎干细胞群在体内做出明确的心源性承诺的能力 发育中的胚状体，在内胚层定向的心肌营养信号传导的短暂窗口期间， 由此产生的中胚层规格产生祖“心脏生成”干细胞 表型。目标＃1将（i）利用基于胚状体的干细胞分离这种促心源性群体 细胞分化，(ii) 定义其分子身份，以及 (iii) 确定其终末倾向 心肌源性转化。目标 #2 将 (i) 破译内胚层衍生的心肌营养物质 信号传导，（ii）以无胚体的方式招募促心源性心脏生成群体 大规模，以及（iii）在体内验证这种新型干细胞类型的安全性。目标 #3 将 (i) 评估获得的心脏生成干细胞治疗心肌梗塞的疗效，(ii) 确定潜在的修复机制，以及 (iii) 改造干细胞以增强耐受性 强调实现增强的心脏保护效果。基于特征 心脏生成干细胞和心肌营养信号的分析，该提案将剖析 心脏生成的基本过程确保多能性的形成。解剖 分子和细胞水平的心脏发生将进一步整合到治疗中 范式，并转化为器官和生物体水平，用于安全的基于细胞的再生治疗 心肌梗塞。

Myocardial infarction is a leading cause of morbidity with loss of contractile performance precipitated by the limited capacity of heart muscle for self-renewal. The aptitude of embryonic stem cells for differentiation into cardiomyocytes provides an opportunity for regenerative repair. Indeed, the basis for therapeutic use of these quintessential stem cells lies in their inherent pluripotency, yet the distinct ability for multi-lineage differentiation carries the liability of neoplastic growth that outweighs benefit impeding reparative applications. The objective of this proposal is to hone stem cell plasticity in order to nullify malignancy-prone unguided differentiation for safe repair. Preliminary studies demonstrate the aptitude for definitive cardiogenic commitment of an embryonic stem cell population within the developing embryoid body, during a transient window of endoderm-directed cardiotrophic signaling, with the resulting specification of the mesoderm yielding a progenitor "cardiopoietic" stem cell phenotype. Aim #1 will (i) isolate this pro-cardiogenic population utilizing embryoid body-based stem cell differentiation, (ii)define its molecular identity, and (iii)determine its propensity for terminal cardiomyogenic transformation. Aim #2 will (i) decipher the endoderm-derived cardiotrophic signaling, (ii) recruit in an embryoid body-free manner the pro-cardiogenic cardiopoietic population at large scale, and (iii) validate in vivo the safety profile of this novel stem cell type. Aim #3 will (i) assess the curative potential of procured cardiopoietic stem cells in treating myocardial infarction,(ii) determine the underlying mechanism for repair, and (iii) engineer stem cells for augmented tolerance to stress achieving enhanced cardioprotective outcome. Based on the characterization of cardiopoietic stem cells and the profiling of cardiotrophic cues, this proposal will dissect the fundamental process of cardiopoiesis securing formative confinement of pluripotency. Dissection of cardiogenesis at the molecular and cellular level will be further integrated into a therapeutic paradigm, and translated to the organ and organism level for safe cell-based regenerative therapy of myocardial infarction.