Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium.
Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium.
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多能干细胞衍生的心肌细胞的旁分泌作用损伤心肌。
DOI：
10.1161/circresaha.117.310803
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发表时间：
2017-09-01
影响因子：
20.1
通讯作者：
Yang PC
中科院分区：
文献类型：
--
作者：
Tachibana A;Santoso MR;Mahmoudi M;Shukla P;Wang L;Bennett M;Goldstone AB;Wang M;Fukushi M;Ebert AD;Woo YJ;Rulifson E;Yang PC
来源于多能干细胞的心肌细胞已被证明具有减轻梗死心肌损伤和改善左心室射血分数（LVEF）的潜力。然而，功能性益处的机制尚不清楚。评价心肌损伤（MI）后移植心脏谱系分化衍生物是否比未分化多能干细胞更有效地增强心肌活力和恢复LVEF。本文中，我们在鼠MI模型中利用人胚胎干细胞（hESC）、hESC衍生的心肌细胞（hCM）、人诱导多能干细胞（iPSC）和iPSC衍生的心肌细胞（iCM）的新型多模态评价。在免疫抑制小鼠中诱导永久结扎左前降支冠状动脉。用（1）hESC（n=9）、（2）iPSC（n=8）、（3）hCM（n=9）、（4）iCM（n=14）和（5）PBS对照（n=10）进行心肌内注射。分别通过心脏MRI和锰增强MRI（MEMRI）测量的LVEF和心肌存活率，与多能干细胞或对照治疗的小鼠相比，hCM和iCM治疗的小鼠显著改善。生物发光成像（BLI）显示所有处理组中有限的细胞植入，表明细胞分泌物可能是修复机制的基础。为了确定移植细胞的旁分泌效应，在体外评估来自所有组的上清液的细胞因子。小鼠心肌的基因表达和免疫组织化学分析表明，与多能干细胞和对照组相比，用心脏谱系细胞处理的组中促迁移、促血管生成和抗凋亡靶点显著上调。这项研究表明，hCM和iCM的心脏表型通过其差异旁分泌效应比未分化干细胞更有效地挽救受损心肌。
Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction (LVEF). However, the mechanism underlying the functional benefit is unclear. To evaluate whether the transplantation of cardiac lineage differentiated derivatives enhance myocardial viability and restore LVEF more effectively than undifferentiated pluripotent stem cells after a myocardial injury (MI). Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine MI model. Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intra-myocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14) and (5) PBS control (n=10). LVEF and myocardial viability, measured by cardiac-MRI and manganese-enhanced MRI (MEMRI), respectively, was significantly improved in hCM- and iCM-treated mice compared to pluripotent stem cell- or control-treated mice. Bioluminescence imaging (BLI) revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant up-regulation of the pro-migratory, pro-angiogenic, and anti-apoptotic targets in groups treated with cardiac lineage cells compared to pluripotent stem cell and control groups. This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium more effectively than undifferentiated stem cells through their differential paracrine effects.