Refining Cardiac Progenitor Cells for Myocardial Repair

 描述(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的瘢痕所取代，人们对再生病变心肌的策略产生了极大的兴趣。细胞疗法吸引人的是提供理想的细胞来再生受损的心脏；然而，到目前为止，临床试验的结果还没有显示出在大多数情况下细胞疗法有明显的好处。缺乏可靠的临床益处可能是由于多种因素，但特别是我们建议，最佳的细胞制剂尚未经过测试。形成新心肌的能力最强的细胞群体是心脏发育过程中存在的心脏前体细胞。因此，我们的中心假设是，可以从天然心脏或多能干细胞中分离出不同群体的心脏前体细胞，以及通过直接重新编程体细胞，与分化细胞类型相比，体细胞将显示出更好的修复受损心肌的能力。然而，我们对导致心脏发育的不同心脏前体细胞群体的了解还不完全，我们分离这些心脏前体细胞的能力是有限的。我们建议从三个目标中解决这些限制：1)从发育中的小鼠心脏和小鼠胚胎干细胞中鉴定和分离第一心区、左室祖细胞；2)CPC的测试移植，并在心肌梗死后的心脏修复中直接体内重编程为ICPC；以及3)产生增殖的、多潜能的人类诱导的CPC。这项研究将促进我们对心脏前体细胞的了解，为CPC的分离和研究提供新的工具，并测试强有力的心肌梗死后心脏修复的新方法。

 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.