Engineering human cardiac stem cells for therapeutic applications in heart disease

心脏具有最小的再生能力，并且在梗塞后遭受永久性损伤和肌肉损失。在移植细胞可能具有强大的心肌生成潜能的前提下，外源性使用干细胞修复受损的心脏已有很长的历史。由于已经发现，所使用的成体干细胞类型实际上几乎没有能力制造新的心肌，因此这些治疗方法所取得的非常有限的益处不再令人惊讶。然而，与成人干细胞相比，人类胚胎干细胞和诱导多能干细胞（hPSCs）具有制造包括真正的心肌细胞在内的所有细胞类型的能力，因此在心脏再生医学方面具有更大的潜力。由于梗死后大约有10亿个心肌细胞丢失，有效的细胞治疗可能不仅需要有效的植入，还需要移植后的扩张潜力。直到最近，人类造血干细胞衍生的心脏祖细胞（CPCs）的扩增是无法实现的，但利用基因操作现在已经成为可能。采用独特的多学科方法，本项目旨在通过设计心脏细胞身份（表观遗传状态/基因表达）以及细胞的生物物理微环境来克服移植的基本挑战，从而在心脏再生医学方面取得重要进展。

The heart has minimal regenerative capacity and suffers permanent damage and muscle loss after an infarction. The exogenous use of stem cells to repair the damaged heart has a long history founded on the premise that the transplanted cells might have potent cardiomyogenic potential. As it has emerged that the adult stem cell types being used in fact have very little capacity to make new myocardium1, the very modest benefits achieved by these treatments are no longer surprising. However, in comparison to stem cells of adult origin, human embryonic and induced pluripotent stem cells (hPSCs) have the capacity to make all cell types including bona fide cardiomyocytes and therefore offer much more profound potential for cardiac regenerative medicine. As approximately one billion cardiomyocytes are lost following an infarction, an effective cell therapy may require not only efficient engraftment but also post-transplant expansion potential. Until recently the expansion of hPSC-derived cardiac progenitor cells (CPCs) was unachievable2, but using genetic manipulation this is now possible3. Taking a unique multidisciplinary approach, this project aims to overcome fundamental challenges by engineering cardiac cell identity (epigenetic status/gene expression) as well as the cells' biophysical microenvironment on transplantation, to deliver crucial advances in cardiac regenerative medicine.