YAP Induces Human Naive Pluripotency

• Main Authors: Han Qin, Miroslav Hejna, Yanxia Liu, Michelle Percharde, Mark Wossidlo, Laure Blouin, Jens Durruthy-Durruthy, Priscilla Wong, Zhongxia Qi, Jingwei Yu, Lei S. Qi, Vittorio Sebastiano, Jun S. Song, Miguel Ramalho-Santos
• Format: Article
• Language: English
• Published: Elsevier 2016-03-01
• Series: Cell Reports
• Subjects: embryonic stem cells (ESCs); induced pluripotent stem cells (iPSCs); pluripotent stem cells (PSCs); naive pluripotency; Hippo pathway; Yes-associated protein (YAP); lysophosphatidic acid (LPA)
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124716301395

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.