Cardiac Repair of Severe Heart Failure by Human Heart- or Skeletal Muscle-Derived Multipotent Stem Cells

最近的研究表明，来自成人心脏的心脏干细胞(CSCs)可以分化为具有功能的心肌细胞；然而，识别CSCs特定单一实体的特定表面标志物及其调控其生长的分子机制仍不清楚。在这里，我们展示了一种单细胞沉积分析，从成人心脏中分离单独选择的CSCs，并研究它们增殖和存活所需的信号。克隆增殖的CSCs表达干细胞抗原-1(SCA-1)，具有胚胎干细胞和间充质细胞样的特征，并与端粒酶逆转录酶(TERT)相关。使用在TERT启动子控制下表达GFP报告基因的转基因，我们证明了心脏的TERT^&lt；GFP+&gt；组分被诱捕到表达SCA-1的细胞。CSCs中SCA-1转录本的敲除通过Akt失活导致抑制体外扩增和细胞凋亡。我们还发现，CSC直接移植到缺血心肌后持续的增殖和存活需要SCA-1上调分泌的旁分泌效应，从而促进新生血管的生成和限制心脏细胞的凋亡，因此，SCA-1可能是促进CSC增殖和存活的重要成分，直接促进CSC的早期植入，并间接影响CSC移植后的晚期心血管分化。

Recent studies have shown that cardiac stem cells (CSCs) from the adult heart can give rise to functional cardiomyocytes; however, the definite surface markers to identify a definitive single entity of CSCs and the molecular mechanisms regulating their growth have remained unknown. Here we demonstrate a single-cell deposition analysis to isolate individually selected CSCs from adult hearts and investigate the signals required for their proliferation and survival. Clonally proliferated CSCs express stem cell antigen-1 (Sca-1) with embryonic stem (ES) cell-and mesenchymal cell-like characteristics and are associated with telomerase reverse transcriptase (TERT). Using a transgene that expresses a GFP reporter under the control of the TERT promoter, we demonstrated that TERT^<GFP+> fractions from the heart were entiched for cell expressing Sca-1. Knockdown of Sca-1 transcripts in CSCs led to retarded ex vivo expansion and apoptosis through Akt inactivation. We also show that ongoing CSC proliferation and survival after direct cell-grafting into ischemic myocardium require Sca-1 to upregulate the secreted paracrine effectors that augment neoangiogenesis and limit cardiac apoptosis, Thus, Sca-1 might bean essential component that promotes CSC proliferation and survival to directly facilitate early engraftment, and that indirectly exerts the effects on late cardiovascular differentiation after CSC transplantation.