Molecular Criteria for Defining the Naive Human Pluripotent State

Cell Stem Cell. 2016 Oct 6;19(4):502-515. doi: 10.1016/j.stem.2016.06.011. Epub 2016 Jul 14.


Recent studies have aimed to convert cultured human pluripotent cells to a naive state, but it remains unclear to what extent the resulting cells recapitulate in vivo naive pluripotency. Here we propose a set of molecular criteria for evaluating the naive human pluripotent state by comparing it to the human embryo. We show that transcription of transposable elements provides a sensitive measure of the concordance between pluripotent stem cells and early human development. We also show that induction of the naive state is accompanied by genome-wide DNA hypomethylation, which is reversible except at imprinted genes, and that the X chromosome status resembles that of the human preimplantation embryo. However, we did not see efficient incorporation of naive human cells into mouse embryos. Overall, the different naive conditions we tested showed varied relationships to human embryonic states based on molecular criteria, providing a backdrop for future analysis of naive human pluripotency.

Keywords: DNA methylation; X chromosome reactivation; embryonic stem cells; imprinting; mouse-human chimeras; pluripotency; transposable elements.

Publication types

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

MeSH terms

  • Animals
  • Blastocyst / cytology
  • Blastocyst / metabolism
  • Cell Differentiation / genetics
  • Cell Line
  • Chimera / metabolism
  • Chromosomes, Human, X / genetics
  • Cleavage Stage, Ovum / metabolism
  • DNA Methylation / genetics
  • DNA Transposable Elements / genetics
  • DNA, Mitochondrial / metabolism
  • Female
  • Gene Expression Profiling
  • Genome, Human
  • Genomic Imprinting
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mitochondria / metabolism
  • Morula / cytology
  • Morula / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Polymerase Chain Reaction
  • Transcription, Genetic


  • DNA Transposable Elements
  • DNA, Mitochondrial