Inhibition of β-catenin signaling respecifies anterior-like endothelium into beating human cardiomyocytes.
Inhibition of β-catenin signaling respecifies anterior-like endothelium into beating human cardiomyocytes.
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DOI：
10.1242/dev.117010
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Murry CE
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文献类型：
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作者：
Palpant NJ;Pabon L;Roberts M;Hadland B;Jones D;Jones C;Moon RT;Ruzzo WL;Bernstein I;Zheng Y;Murry CE
在脊椎动物发育过程中，中胚层命运的选择是由形态因子（如激活素/结蛋白、bmp和Wnt/β-连环蛋白）之间的相互作用调节的，这些形态因子定义了前后模式，并指定了下游衍生物，包括心肌细胞、内皮细胞和造血细胞。我们使用人类胚胎干细胞来探索这些途径如何在体外控制中胚层的命运选择。不同剂量的激活素A和BMP4来模拟胚胎前后轴的细胞因子梯度极化，导致Wnt/β-catenin信号的不同活性，并指定不同的前样（高激活素/低BMP）和后样（低激活素/高BMP）中胚层群体。心源性中胚层是在特定的前样中胚层条件下生成的，而造血内皮是由后样中胚层生成的，血管形成的CD31+内皮细胞是由所有中胚层来源生成的。令人惊讶的是，β-catenin信号的抑制导致前样内皮高效地重新规范为跳动的心肌细胞。在后源性内皮细胞中未观察到心脏再分化。因此，激活素/BMP梯度指定了不同的中胚层亚群，这些亚群产生具有独特血管生成、血液生成和心脏生成特性的细胞衍生物，这对于理解胚胎发生和开发治疗方法是有用的。摘要：控制胚胎模式的信号的操纵允许人类多能干细胞分化成内皮亚群，具有不同的造血、血管生成和心脏生成潜力。
During vertebrate development, mesodermal fate choices are regulated by interactions between morphogens such as activin/nodal, BMPs and Wnt/β-catenin that define anterior-posterior patterning and specify downstream derivatives including cardiomyocyte, endothelial and hematopoietic cells. We used human embryonic stem cells to explore how these pathways control mesodermal fate choices in vitro. Varying doses of activin A and BMP4 to mimic cytokine gradient polarization in the anterior-posterior axis of the embryo led to differential activity of Wnt/β-catenin signaling and specified distinct anterior-like (high activin/low BMP) and posterior-like (low activin/high BMP) mesodermal populations. Cardiogenic mesoderm was generated under conditions specifying anterior-like mesoderm, whereas blood-forming endothelium was generated from posterior-like mesoderm, and vessel-forming CD31+ endothelial cells were generated from all mesoderm origins. Surprisingly, inhibition of β-catenin signaling led to the highly efficient respecification of anterior-like endothelium into beating cardiomyocytes. Cardiac respecification was not observed in posterior-derived endothelial cells. Thus, activin/BMP gradients specify distinct mesodermal subpopulations that generate cell derivatives with unique angiogenic, hemogenic and cardiogenic properties that should be useful for understanding embryogenesis and developing therapeutics. Summary: The manipulation of signals that control embryonic patterning allows human pluripotent stem cells to be differentiated into endothelial subpopulations with distinct haematopoietic, angiogenic and cardiogenic potential.