title: YAP Induces Human Naive Pluripotency.
abstract: 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.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Ob/Gyn and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Qin
authors.affiliation: Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA; Departments of Bioengineering and Physics, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Hejna
authors.affiliation: Departments of Bioengineering and Chemical and Systems Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; ChEM-H, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Ob/Gyn and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Percharde
authors.affiliation: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; Departments of Genetics and Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wossidlo
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Ob/Gyn and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Blouin
authors.affiliation: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; Departments of Genetics and Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Durruthy-Durruthy
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Ob/Gyn and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Wong
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Yu
authors.affiliation: Departments of Bioengineering and Chemical and Systems Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; ChEM-H, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Lei S
authors.initials: LS
authors.lastname: Qi
authors.affiliation: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; Departments of Genetics and Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sebastiano
authors.affiliation: Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA; Departments of Bioengineering and Physics, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Song
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Ob/Gyn and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: mrsantos@ucsf.edu.
authors.forename: Miguel
authors.initials: M
authors.lastname: Ramalho-Santos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D064113:CRISPR-Cas Systems / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D059785:Karyotype; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D013724:Teratoma / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; C473711:Chir 99021; D006570:Heterochromatin; D008246:Lysophospholipids; D010750:Phosphoproteins; D011725:Pyridines; D011743:Pyrimidines; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C506614:mirdametinib; D004159:Diphenylamine; D038362:Glycogen Synthase Kinase 3; C032881:lysophosphatidic acid
keywords: Hippo pathway; Yes-associated protein (YAP); embryonic stem cells (ESCs); induced pluripotent stem cells (iPSCs); lysophosphatidic acid (LPA); naive pluripotency; pluripotent stem cells (PSCs)