Cardioprotective Repair through Cardiopoiesis

心肌梗死是导致心肌收缩功能丧失的主要原因 是因为心肌自我更新的能力有限胚胎干细胞的能力 分化成心肌细胞提供了再生修复的机会。事实上，基础 这些典型的干细胞的治疗用途在于其固有的多能性，但不同的是， 多谱系分化的能力带来了肿瘤生长的可能性， 阻碍了赔偿申请。这项提议的目的是磨练干细胞的可塑性， 以消除恶性倾向的无指导分化，从而进行安全修复。初步研究表明， 胚胎干细胞群体在胚胎干细胞中的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， 结果中胚层的特化产生祖“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该促心源性群体 细胞分化，（ii）定义其分子身份，和（iii）确定其终末分化倾向， 心肌性转化目标#2将（i）破译内胚层来源的心肌营养因子， 信号传导，（ii）以无胚状体的方式募集促心源性心脏生成群体 在大规模，和（iii）在体内验证这种新的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在治疗心肌梗死中的治疗潜力，（ii） 确定修复的潜在机制，以及（iii）工程干细胞以增强耐受性 以强调实现增强的心脏保护效果。基于对 心脏造血干细胞和心脏营养线索的分析，这项建议将剖析 心脏生成的基本过程，确保多能性的形成限制。解剖 分子和细胞水平的心脏发生将进一步整合到治疗中， 范例，并转化为器官和生物体水平的安全细胞为基础的再生治疗， 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.