Regulatory Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Regulatory Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Stem Cell Reports. 2018 Dec 11;11(6):1357-1364. doi: 10.1016/j.stemcr.2018.10.013. Epub 2018 Nov 15.
Specifying the primitive streak (PS) guides stem cell differentiation in vitro; however, much remains to be learned about the transcription networks that direct anterior and posterior PS cells (APS and PPS, respectively) to differentiate to distinct mesendodermal subpopulations. Here, we show that APS genes are predominantly induced in YAP1 human embryonic stem cells (hESCs) in response to ACTIVIN. This finding establishes the Hippo effector YAP1 as a master regulator of PS specification, functioning to repress ACTIVIN-regulated APS genes in hESCs. Moreover, transient exposure of wild-type hESCs to dasatinib, a potent C-SRC/YAP1 inhibitor, enables differentiation to APS-derived endoderm and cardiac mesoderm in response to ACTIVIN. Importantly, these cells can differentiate efficiently to normal beating cardiomyocytes without the cytoskeletal defect seen in YAP1 hESC-derived cardiomyocytes. Overall, we uncovered an induction mechanism to generate APS cells using a cocktail of ACTIVIN and YAP1i molecules that holds practical implications for hESC and induced pluripotent stem cell differentiation into distinct mesendodermal lineages.
原肠胚（PS）指定指导干细胞在体外分化; 然而，关于指导前PS 细胞（APS）和后 PS 细胞（PPS）分化为不同的中胚层亚群的转录网络，仍有许多需要了解。在这里，我们表明，在 ACTIVIN 响应下，YAP1 人胚胎干细胞（hESCs）中主要诱导 APS 基因。这一发现确立了 Hippo 效应物 YAP1 作为 PS 规范的主要调节剂，其功能是在 hESCs 中抑制 ACTIVIN 调节的 APS 基因。此外，瞬时暴露于强效 C-SRC/YAP1 抑制剂达沙替尼的野生型 hESCs 能够响应 ACTIVIN 分化为 APS 衍生的内胚层和心脏中胚层。重要的是，这些细胞可以有效地分化为正常搏动的心肌细胞，而不会出现 YAP1 hESC 衍生的心肌细胞中所见的细胞骨架缺陷。总体而言，我们使用 ACTIVIN 和 YAP1i 分子的鸡尾酒发现了一种诱导 APS 细胞的诱导机制，这对 hESC 和诱导多能干细胞分化为不同的中胚层谱系具有实际意义。
