Refining Cardiac Progenitor Cells for Myocardial Repair

 描述（由申请人提供）：在美国，心脏病仍然是最常见的死亡原因。由于大面积心肌梗死后大量的功能性肌肉被纤维化瘢痕所取代，因此对再生患病心肌的策略产生了极大的兴趣。细胞疗法很有吸引力，可以提供理想地再生受损心脏的细胞;然而，迄今为止的临床试验结果在大多数情况下都没有显示出细胞疗法的明显益处。缺乏稳健的临床益处可能是由于多种因素，但特别是我们建议尚未测试最佳细胞制剂。具有形成新心肌的最强能力的细胞群是在心脏发育期间存在的心脏祖细胞。因此，我们的中心假设是，可以从天然心脏或多能干细胞以及通过体细胞的直接重编程分离不同的心脏祖细胞群体，与分化的细胞类型相比，所述体细胞将表现出上级修复受损心肌的能力。然而，我们对负责发育心脏的不同心脏祖细胞群体的了解并不完全，并且我们分离这些心脏祖细胞的能力有限。我们提出在三个目标中解决这些限制：1）从发育中的小鼠心脏和mESC中鉴定和分离第一心野、左心室祖细胞; 2）测试CPC的移植并在MI后心脏修复中直接体内重编程为iCPC;以及3）产生增殖的、多能的人诱导CPC。这项研究将促进我们对心脏祖细胞的理解，为CPC的分离和研究提供新的工具，并测试MI后心脏修复的强大新方法。

 DESCRIPTION (provided by applicant): In the US, heart disease remains the most common cause of death. Because a large volume of functional muscle is replaced by fibrotic scar following a large myocardial infarction, there has been tremendous interest in strategies to regenerate the diseased myocardium. Cell therapy is appealing to provide cells that will ideally regenerate the damaged heart; however, the results of clinical trials to date have not shown clear benefit in most cases from cell therapy. The lack of robust clinical benefit could be due to multiple factors, but particularly we suggest that the optimal cell preparations have not been tested. The cell populations with the most robust capacity to form new cardiac muscle are cardiac progenitors present during heart development. Therefore, our central hypothesis is that distinct populations of cardiac progenitor cells can be isolated from the native heart or pluripotent stem cells as well as by direct reprogramming of somatic cells that will exhibit superior ability to repair the injured myocardium compared to differentiated cell types. However, we have incomplete understanding of the distinct cardiac progenitor populations responsible for the developing heart, and our ability to isolate these cardiac progenitors is limited. We propose to address these limitations in three aims: 1) identify and isolate first heart field, left ventriclar progenitor cells from developing mouse heart and mESCs; 2) test transplantation of CPCs and direct in vivo reprogramming to iCPCs in cardiac repair post-MI; and 3) generate proliferative, multipotent human induced CPCs. This research will advance our understanding of cardiac progenitors, provide new tools for the isolation and study of CPCs, and test powerful new approaches for post-MI cardiac repair.