Modulation of Calcium-Activated Potassium Channels Induces Cardiogenesis of Pluripotent Stem Cells and Enrichment of Pacemaker-Like Cells
Modulation of Calcium-Activated Potassium Channels Induces Cardiogenesis of Pluripotent Stem Cells and Enrichment of Pacemaker-Like Cells
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DOI：
10.1161/circulationaha.110.971721
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发表时间：
2010-11-02
期刊：
影响因子：
37.8
通讯作者：
Liebau, Stefan
中科院分区：
文献类型：
--
作者：
Kleger, Alexander;Seufferlein, Thomas;Liebau, Stefan
背景离子通道是兴奋细胞功能的关键决定因素，但对它们在心脏发育中的作用和参与知之甚少。早期的工作确定了钙激活的小和中等电导钾通道（SKCas）作为神经干细胞命运的重要调节因子。在这里，我们研究了它们对多能细胞向心脏谱系分化的影响。方法和结果-我们将SKCa激活剂1-乙基-2-苯并咪唑啉酮应用于胚胎干细胞，并将这种特定的离子通道家族鉴定为参与心脏起搏器样细胞生成的新的关键靶点：SKCa激活导致肌动蛋白细胞骨架的快速重塑、增殖抑制、分化诱导和减少畸胎瘤形成。时间限制SKCa激活诱导心脏中胚层和承诺的心脏谱系所示的基因调控，蛋白质，和功能电生理研究。此外，向心肌细胞的分化以定性方式进行调节，导致起搏器样细胞的强烈富集。这伴随着窦房基因程序的诱导，同时伴随着室特异性心肌的丧失。此外，SKCa活性诱导激活的Ras-Mek-Erk信号级联，参与1-乙基-2-苯并咪唑啉酮诱导的effects.Conclusions-SKCa激活驱动的命运多能细胞向中胚层承诺和心肌细胞的规格，优先进入神经元样心肌细胞。这为心肌细胞的富集提供了一种新的策略，特别是在没有遗传修饰的情况下产生特定亚型的心肌细胞，即起搏器样细胞。（循环。2010;122：1823-1836.）
Background-Ion channels are key determinants for the function of excitable cells, but little is known about their role and involvement during cardiac development. Earlier work identified Ca2+ -activated potassium channels of small and intermediate conductance (SKCas) as important regulators of neural stem cell fate. Here we have investigated their impact on the differentiation of pluripotent cells toward the cardiac lineage.Methods and Results-We have applied the SKCa activator 1-ethyl-2-benzimidazolinone on embryonic stem cells and identified this particular ion channel family as a new critical target involved in the generation of cardiac pacemaker-like cells: SKCa activation led to rapid remodeling of the actin cytoskeleton, inhibition of proliferation, induction of differentiation, and diminished teratoma formation. Time-restricted SKCa activation induced cardiac mesoderm and commitment to the cardiac lineage as shown by gene regulation, protein, and functional electrophysiological studies. In addition, the differentiation into cardiomyocytes was modulated in a qualitative fashion, resulting in a strong enrichment of pacemaker-like cells. This was accompanied by induction of the sino-atrial gene program and in parallel by a loss of the chamber-specific myocardium. In addition, SKCa activity induced activation of the Ras-Mek-Erk signaling cascade, a signaling pathway involved in the 1-ethyl-2-benzimidazolinone-induced effects.Conclusions-SKCa activation drives the fate of pluripotent cells toward mesoderm commitment and cardiomyocyte specification, preferentially into nodal-like cardiomyocytes. This provides a novel strategy for the enrichment of cardiomyocytes and in particular, the generation of a specific subtype of cardiomyocytes, pacemaker-like cells, without genetic modification. (Circulation. 2010;122:1823-1836.)