Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
J Mol Cell Cardiol. 2012 Mar;52(3):650-9. doi: 10.1016/j.yjmcc.2011.11.010. Epub 2011 Nov 29.
The efficient induction of cardiomyocyte differentiation from embryonic stem (ES) cells is crucial for cardiac regenerative medicine. Although Wnts play important roles in cardiac development, complex questions remain as to when, how and what types of Wnts are involved in cardiogenesis. We found that Wnt2 was strongly up-regulated during cardiomyocyte differentiation from ES cells. Therefore, we investigated when and how Wnt2 acts in cardiogenesis during ES cell differentiation. Wnt2 was strongly expressed in the early developing murine heart. We applied this embryonic Wnt2 expression pattern to ES cell differentiation, to elucidate Wnt2 function in cardiomyocyte differentiation. Wnt2 knockdown revealed that intrinsic Wnt2 was essential for efficient cardiomyocyte differentiation from ES cells. Moreover, exogenous Wnt2 increased cardiomyocyte differentiation from ES cells. Interestingly, the effects on cardiogenesis of intrinsic Wnt2 knockdown and exogenous Wnt2 addition were temporally restricted. During cardiomyocyte differentiation from ES cells, Wnt2 didn't activate canonical Wnt pathway but utilizes JNK/AP-1 pathway which is required for cardiomyocyte differentiation from ES cells. Therefore we conclude that Wnt2 plays strong positive stage-specific role in cardiogenesis through non-canonical Wnt pathway in murine ES cells.
胚胎干细胞（ES 细胞）向心肌细胞的高效诱导分化对于心脏再生医学至关重要。尽管 Wnts 在心脏发育中发挥着重要作用，但关于何时、如何以及哪种类型的 Wnts 参与了心肌发生，仍存在复杂的问题。我们发现 Wnt2 在 ES 细胞向心肌细胞分化过程中强烈上调。因此，我们研究了 Wnt2 在 ES 细胞分化过程中何时以及如何在心肌发生中发挥作用。Wnt2 在早期发育的鼠心中强烈表达。我们将这种胚胎 Wnt2 表达模式应用于 ES 细胞分化，以阐明 Wnt2 在心肌细胞分化中的功能。Wnt2 敲低表明内源性 Wnt2 对于 ES 细胞向心肌细胞的高效分化是必不可少的。此外，外源性 Wnt2 增加了 ES 细胞向心肌细胞的分化。有趣的是，内源性 Wnt2 敲低和外源性 Wnt2 添加对心肌发生的影响在时间上是有限的。在 ES 细胞向心肌细胞的分化过程中，Wnt2 并没有激活经典的 Wnt 通路，而是利用了 JNK/AP-1 通路，该通路对于 ES 细胞向心肌细胞的分化是必需的。因此，我们得出结论，Wnt2 通过非经典的 Wnt 通路在鼠 ES 细胞中发挥强烈的阳性阶段特异性作用，促进心肌发生。
