Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/β-catenin, Activin/Nodal and BMP signaling
Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/β-catenin, Activin/Nodal and BMP signaling
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DOI：
10.1242/dev.021121
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发表时间：
2008-09-01
期刊：
影响因子：
4.6
通讯作者：
Suemori, Hirofumi
中科院分区：
文献类型：
--
作者：
Sumi, Tomoyuki;Tsuneyoshi, Norihiro;Suemori, Hirofumi
经典的Wnt/β-catenin信号在胚胎发育、干细胞自我更新和癌症进展中具有显著不同的作用。在这里，我们发现β-连环蛋白的稳定表达扰乱了人类胚胎干细胞(HES)的自我更新，使得高达80%的HES细胞发育成原始条纹(PS)/中胚层前体细胞，这让人想起早期哺乳动物的胚胎发生。PS/中胚层前体细胞的形成主要依赖于β-连环蛋白与激活素/结节和骨形态发生蛋白信号通路的协同作用。有趣的是，BMP信号的阻断完全取消了中胚层的生成，并诱导了细胞命运向PS前体细胞的转变。PI3-Kinase/Akt信号通路，而不是MAPK信号通路，至少部分通过增强β-catenin的稳定性，在PS的前部调控中起着关键作用。此外，激活素/Nodal和Wnt/β-catenin信号协同诱导前PS/内胚层的产生和规范。综上所述，我们的发现清楚地表明，激活素/节点和骨形态发生蛋白信号的协调平衡决定了HES细胞中规范的Wnt/β-catenin信号诱导的新生PS的细胞命运。
The canonical Wnt/beta-catenin signaling has remarkably diverse roles in embryonic development, stem cell self-renewal and cancer progression. Here, we show that stabilized expression of beta-catenin perturbed human embryonic stem (hES)-cell self-renewal, such that up to 80% of the hES cells developed into the primitive streak (PS)/mesoderm progenitors, reminiscent of early mammalian embryogenesis. The formation of the PS/mesoderm progenitors essentially depended on the cooperative action of beta-catenin together with Activin/Nodal and BMP signaling pathways. Intriguingly, blockade of BMP signaling completely abolished mesoderm generation, and induced a cell fate change towards the anterior PS progenitors. The PI3-kinase/Akt, but not MAPK, signaling pathway had a crucial role in the anterior PS specification, at least in part, by enhancing beta-catenin stability. In addition, Activin/Nodal and Wnt/beta-catenin signaling synergistically induced the generation and specification of the anterior PS/endoderm. Taken together, our findings clearly demonstrate that the orchestrated balance of Activin/Nodal and BMP signaling defines the cell fate of the nascent PS induced by canonical Wnt/beta-catenin signaling in hES cells.