Pluripotent state transitions coordinate morphogenesis in mouse and human embryos.

Abstract

The foundations of mammalian development lie in a cluster of embryonic epiblast stem cells that, in response to extracellular matrix signalling, undergo epithelialization creating an apical surface in contact with a cavity1,2, a fundamental event for all subsequent development. Concomitantly, epiblast cells transit through distinct pluripotent states3,4, before lineage commitment at gastrulation. These pluripotent states have been characterized at the molecular level5, but their biological importance remains unclear. Here we show that exit from an unrestricted naive pluripotent state is required for epiblast epithelialization and generation of the pro-amniotic cavity in mouse embryos. Embryonic stem cells locked in the naive state are able to initiate polarization but fail to undergo lumenogenesis. Mechanistically, exit from naive pluripotency activates an Oct4-governed transcriptional program resulting in expression of glycosylated sialomucin proteins and the vesicle tethering and fusion events of lumenogenesis. Similarly, culture of human embryos beyond implantation reveals that exit from naive pluripotency triggers amniotic cavity formation and developmental progression. Our results add tissue-level architecture as a new criterion for the characterization of different pluripotent states, and show the relevance of transitions between these states during development of the mammalian embryo.