Cardioprotective Repair through Cardiopoiesis

心肌梗死是发病率的主要原因，导致收缩功能丧失。 心肌的自我更新能力有限。胚胎干细胞的能力 分化为心肌细胞为再生修复提供了机会。事实上，其基础是 对于这些典型的干细胞的治疗用途在于它们固有的多能性，但独特的 多谱系分化的能力带来的是肿瘤生长的缺陷，而不是益处 阻碍修复性应用。这项建议的目标是有序地磨练干细胞的可塑性。 为了安全修复，使易发生恶性肿瘤的非引导分化无效。初步研究表明 胚胎干细胞群体中明确的心源性承诺的能力 在内胚层导向的心脏营养信号的短暂窗口中，发育类胚体， 由此产生的中胚层规格产生了一种祖细胞“造心”干细胞 表型。目标1将(I)利用类胚体干细胞分离这一促心源性人群 细胞分化，(Ii)确定其分子特性，以及(Iii)确定其终末倾向 心肌转化。目的#2将(I)破译内胚层来源的心肌营养 信号，(2)以类胚体脱体的方式招募促心源性心脏生成的人群 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) 评估获得的心脏造血干细胞治疗心肌梗死的潜力，(Ii) 确定修复的潜在机制，以及(Iii)设计干细胞以增强耐受性 强调实现增强的心脏保护效果。基于以下特征： 心脏干细胞和心肌营养线索的概况，这项提案将剖析 心脏生成的基本过程确保多能性的形成限制。剖析 分子和细胞层面的心脏发生将进一步整合到一种治疗方法中 范例，并转化到器官和生物水平，用于安全的基于细胞的再生治疗 心肌梗死。

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.