YAP Induces Human Naive Pluripotency.
YAP Induces Human Naive Pluripotency.
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DOI：
10.1016/j.celrep.2016.02.036
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发表时间：
2016-03-15
期刊：
影响因子：
8.8
通讯作者：
Ramalho-Santos M
中科院分区：
文献类型：
--
作者：
Qin H;Hejna M;Liu Y;Percharde M;Wossidlo M;Blouin L;Durruthy-Durruthy J;Wong P;Qi Z;Yu J;Qi LS;Sebastiano V;Song JS;Ramalho-Santos M
人幼稚多能干细胞（PSC）状态，对应于发育的植入前阶段，一直难以在体外捕获和维持。我们报告说，河马途径效应雅普是核定位在人类囊胚的内细胞团。雅普在人胚胎干细胞（ESC）和诱导的PSC（iPSC）中的过表达促进幼稚PSC的产生。溶血磷脂酸（LPA）可以部分替代雅普以产生无转基因的人幼稚PSC。雅普或LPA诱导的幼稚PSC具有快速的克隆生长速率、正常的核型、形成畸胎瘤的能力、与人植入前胚胎的转录相似性、降低的异染色质水平和幼稚状态的其他标志。雅普/LPA部分通过抑制GSK 3抑制的分化诱导作用而起作用。CRISPR/Cas9产生的雅普−/−细胞在初始但未引发的条件下形成集落的能力受损。这些结果揭示了一个意想不到的作用，雅普在人类幼稚状态，与早期人类胚胎学的影响。
The human naive pluripotent stem cell (PSC) state, corresponding to a pre-implantation stage of development, has been difficult to capture and sustain in vitro. We report that the Hippo pathway effector YAP is nuclearly localized in the inner cell mass of human blastocysts. Overexpression of YAP in human embryonic stem cells (ESCs) and induced PSCs (iPSCs) promotes the generation of naive PSCs. Lysophosphatidic acid (LPA) can partially substitute for YAP to generate transgene-free human naive PSCs. YAP- or LPA-induced naive PSCs have a rapid clonal growth rate, a normal karyotype, the ability to form teratomas, transcriptional similarities to human pre-implantation embryos, reduced heterochromatin levels, and other hallmarks of the naive state. YAP/LPA act in part by suppressing differentiation-inducing effects of GSK3 inhibition. CRISPR/Cas9-generated YAP−/− cells have an impaired ability to form colonies in naive but not primed conditions. These results uncover an unexpected role for YAP in the human naive state, with implications for early human embryology.