Stage-Specific Optimization of Activin/Nodal and BMP Signaling Promotes Cardiac Differentiation of Mouse and Human Pluripotent Stem Cell Lines
Stage-Specific Optimization of Activin/Nodal and BMP Signaling Promotes Cardiac Differentiation of Mouse and Human Pluripotent Stem Cell Lines
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DOI：
10.1016/j.stem.2010.12.008
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发表时间：
2011-02-04
期刊：
影响因子：
23.9
通讯作者：
Keller, Gordon
中科院分区：
文献类型：
--
作者：
Kattman, Steven J.;Witty, Alec D.;Keller, Gordon
胚胎干细胞 (ESC) 和诱导多能干细胞 (iPSC) 有效分化为多种谱系需要采用逐步方法来复制胚胎发育过程中发现的关键定型阶段。在这里，我们发现 PdgfR-alpha 的表达将小鼠 ESC 衍生的 Flk-1 中胚层分离为 Flk-1(+)PdgfR-alpha(+) 心脏亚群和 Flk-1(+)PdgfR-alpha(-) 造血亚群。通过监测 Flk-1 和 PdgfR-α 表达，我们发现心脏中胚层和心肌细胞的规格是由 Activin/Nodal 和 BMP 信号传导水平的非常小的变化决定的。向人类 ESC 和 iPSC 的转化表明，心脏中胚层的出现也可以通过 KDR 和 PDGFR-α 的共表达来监测，并且该过程同样依赖于 Activin/Nodal 和 BMP 信号传导的最佳水平。重要的是，我们发现个体小鼠和人类多能干细胞系需要优化这些信号通路以实现有效的心脏分化，这说明了一个很可能适用于其他情况的原理。
Efficient differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to a variety of lineages requires step-wise approaches replicating the key commitment stages found during embryonic development. Here we show that expression of PdgfR-alpha segregates mouse ESC-derived Flk-1 mesoderm into Flk-1(+)PdgfR-alpha(+) cardiac and Flk-1(+)PdgfR-alpha(-) hematopoietic subpopulations. By monitoring Flk-1 and PdgfR-alpha expression, we found that specification of cardiac mesoderm and cardiomyocytes is determined by remarkably small changes in levels of Activin/Nodal and BMP signaling. Translation to human ESCs and iPSCs revealed that the emergence of cardiac mesoderm could also be monitored by coexpression of KDR and PDGFR-alpha and that this process was similarly dependent on optimal levels of Activin/Nodal and BMP signaling. Importantly, we found that individual mouse and human pluripotent stem cell lines require optimization of these signaling pathways for efficient cardiac differentiation, illustrating a principle that may well apply in other contexts.