Molecular Criteria for Defining the Naive Human Pluripotent State

Highlights

• Naive human ESCs share a unique transposon signature with cleavage-stage embryos

• Global DNA demethylation in naive human ESCs is reversible except at imprinted loci

• The X chromosome status of naive human ESCs resembles the preimplantation embryo

• Naive human ESCs incorporate into the mouse morula or blastocyst very inefficiently

Summary

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.