YAP Induces Human Naive Pluripotency

Cell Rep. 2016 Mar 15;14(10):2301-12. doi: 10.1016/j.celrep.2016.02.036. Epub 2016 Mar 3.

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.

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Benzamides / pharmacology
  • Blastocyst / cytology
  • Blastocyst / metabolism
  • Blastocyst / pathology
  • CRISPR-Cas Systems / genetics
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Female
  • Gene Expression Regulation / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Heterochromatin / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Karyotype
  • Lysophospholipids / pharmacology
  • Male
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • RNA Interference
  • Teratoma / metabolism
  • Teratoma / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Wnt Signaling Pathway / drug effects
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Benzamides
  • Chir 99021
  • Heterochromatin
  • Lysophospholipids
  • Phosphoproteins
  • Pyridines
  • Pyrimidines
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • mirdametinib
  • Diphenylamine
  • Glycogen Synthase Kinase 3
  • lysophosphatidic acid