Pivotal Role of Non-cardiomyocytes in Electromechanical and Therapeutic Potential of Induced Pluripotent Stem Cell-Derived Engineered Cardiac Tissue.
Pivotal Role of Non-cardiomyocytes in Electromechanical and Therapeutic Potential of Induced Pluripotent Stem Cell-Derived Engineered Cardiac Tissue.
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DOI：
10.1089/ten.tea.2016.0535
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发表时间：
2018-03
影响因子：
--
通讯作者：
Sawa Y
中科院分区：
文献类型：
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作者：
Iseoka H;Miyagawa S;Fukushima S;Saito A;Masuda S;Yajima S;Ito E;Sougawa N;Takeda M;Harada A;Lee JK;Sawa Y
虽然由诱导多能干细胞（iPSCs）衍生的工程心脏组织（ECTs）在心肌再生治疗中很有前景，但心肌细胞与非心肌细胞的适当比例尚不完全清楚。在这里，我们确定ECT细胞含量是否是其结构/功能的关键决定因素，从而影响ECT治疗晚期心力衰竭的潜力。利用心脏特异性标记物进行磁激活细胞分选，生成ipsc来源心肌细胞不同比例（25%、50%、70%或90%）的无支架细胞内皮细胞。值得注意的是，当心肌细胞占总细胞数的50%以上时，ECTs呈现同步自发跳动，且电传导速度随心肌细胞比例的增加而增加；然而，含有90%心肌细胞的ECTs未能形成稳定的结构。含有25%或50%心肌细胞的ECTs主要表达胶原蛋白和纤维连接蛋白，而含有70%心肌细胞的ECTs主要表达层粘连蛋白，并表现出最高的收缩/松弛特性。此外，将含有50%或70%心肌细胞的ECTs移植到大鼠慢性心肌梗死模型中，与对照组相比，功能恢复更深刻。值得注意的是，移植的ECTs在Langendorff灌注下与原生心脏电同步。总的来说，这些结果表明，非心肌细胞的数量对于生成功能性ipsc衍生的ECTs作为心脏再生治疗的移植物至关重要，含有50-70%心肌细胞的ECTs具有稳定的结构和增加的心脏治疗潜力。
Although engineered cardiac tissues (ECTs) derived from induced pluripotent stem cells (iPSCs) are promising for myocardial regenerative therapy, the appropriate ratio of cardiomyocytes to non-cardiomyocytes is not fully understood. Here, we determined whether ECT-cell content is a key determinant of its structure/function, thereby affecting ECT therapeutic potential for advanced heart failure. Scaffold-free ECTs containing different ratios (25%, 50%, 70%, or 90%) of iPSC-derived cardiomyocytes were generated by magnetic-activated cell sorting by using cardiac-specific markers. Notably, ECTs showed synchronized spontaneous beating when cardiomyocytes constituted ≥50% of total cells, with the electrical-conduction velocity increasing depending on cardiomyocyte ratio; however, ECTs containing 90% cardiomyocytes failed to form stable structures. ECTs containing 25% or 50% cardiomyocytes predominantly expressed collagen and fibronectin, whereas ECTs containing 70% cardiomyocytes predominantly expressed laminin and exhibited the highest contractile/relaxation properties. Furthermore, transplantation of ECTs containing 50% or 70% cardiomyocytes into a rat chronic myocardial infarction model led to a more profound functional recovery as compared with controls. Notably, transplanted ECTs showed electrical synchronization with the native heart under Langendorff perfusion. Collectively, these results indicate that the quantity of non-cardiomyocytes is critical in generating functional iPSC-derived ECTs as grafts for cardiac-regeneration therapy, with ECTs containing 50–70% cardiomyocytes exhibiting stable structures and increased cardiotherapeutic potential.