外泌体中的非编码 RNA 比较和人胚胎干细胞与诱导多能干细胞衍生的心肌细胞的功能功效。
Comparison of Non-Coding RNAs in Exosomes and Functional Efficacy of Human Embryonic Stem Cell- versus Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
机构信息
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.
Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, California, USA.
出版信息
Stem Cells. 2017 Oct;35(10):2138-2149. doi: 10.1002/stem.2669. Epub 2017 Jul 31.
Both human embryonic stem cell-derived cardiomyocytes (ESC-CMs) and human induced pluripotent stem cell-derived CMs (iPSC-CMs) can serve as unlimited cell sources for cardiac regenerative therapy. However, the functional equivalency between human ESC-CMs and iPSC-CMs for cardiac regenerative therapy has not been demonstrated. Here, we performed a head-to-head comparison of ESC-CMs and iPSC-CMs in their ability to restore cardiac function in a rat myocardial infarction (MI) model as well as their exosomal secretome. Human ESCs and iPSCs were differentiated into CMs using small molecule inhibitors. Fluorescence-activated cell sorting analysis confirmed ∼85% and ∼83% of CMs differentiated from ESCs and iPSCs, respectively, were positive for cardiac troponin T. At a single-cell level, both cell types displayed similar calcium handling and electrophysiological properties, with gene expression comparable with the human fetal heart marked by striated sarcomeres. Sub-acute transplantation of ESC-CMs and iPSC-CMs into nude rats post-MI improved cardiac function, which was associated with increased expression of angiogenic genes in vitro following hypoxia. Profiling of exosomal microRNAs (miRs) and long non-coding RNAs (lncRNAs) revealed that both groups contain an identical repertoire of miRs and lncRNAs, including some that are known to be cardioprotective. We demonstrate that both ESC-CMs and iPSC-CMs can facilitate comparable cardiac repair. This is advantageous because, unlike allogeneic ESC-CMs used in therapy, autologous iPSC-CMs could potentially avoid immune rejection when used for cardiac cell transplantation in the future. Stem Cells 2017;35:2138-2149.
人胚胎干细胞来源的心肌细胞(ESC-CMs)和人诱导多能干细胞来源的心肌细胞(iPSC-CMs)均可作为心脏再生治疗的无限细胞来源。然而,ESC-CMs 和 iPSC-CMs 在心脏再生治疗中的功能等效性尚未得到证实。在此,我们在大鼠心肌梗死(MI)模型中以及它们的外泌体分泌组中,对 ESC-CMs 和 iPSC-CMs 恢复心脏功能的能力进行了直接比较。我们使用小分子抑制剂将人 ESC 和 iPSC 分化为心肌细胞。荧光激活细胞分选分析证实,ESC 和 iPSC 分化而来的心肌细胞中,约有 85%和 83%分别对心肌肌钙蛋白 T 呈阳性。在单细胞水平上,两种细胞类型均表现出相似的钙处理和电生理特性,其基因表达与具有条纹肌节的人心率相当。ESC-CMs 和 iPSC-CMs 在 MI 后亚急性移植到裸鼠体内,可改善心脏功能,这与体外缺氧后血管生成基因的表达增加有关。外泌体 microRNAs(miRs)和长非编码 RNA(lncRNAs)的分析显示,两组均包含相同的 miR 和 lncRNA 谱,包括一些已知具有心脏保护作用的 miR 和 lncRNA。我们证明 ESC-CMs 和 iPSC-CMs 均可促进类似的心脏修复。这是有利的,因为与用于治疗的同种异体 ESC-CMs 不同,自体 iPSC-CMs 将来在用于心脏细胞移植时,可能会避免免疫排斥。Stem Cells 2017;35:2138-2149.