Pluripotent state transitions coordinate morphogenesis in mouse and human embryos

Exit of epiblasts from an unrestricted naive pluripotent state is required for epithelialization and generation of the pro-amniotic cavity in mouse embryos and for amniotic cavity formation in human embryos and human embryonic stem cells. Cells stem pluripotent state to grow During mammalian development, embryonic pluripotent stem cells form a cavitated epithelium at the time of implantation. Magdalena Zernicka-Goetz and colleagues show that, in spheroids made from mouse embryonic stem cells, the cells must leave their unrestricted naive pluripotent state for the events leading to cavity formation. The transcription factor Oct4 activates this exit and the expression of genes that code for proteins involved in lumenogenesis. The authors also show that these events are conserved in spheroids from human embryonic stem cells. The foundations of mammalian development lie in a cluster of embryonic epiblast stem cells. In response to extracellular matrix signalling, these cells undergo epithelialization and create an apical surface in contact with a cavity 1 , 2 , a fundamental event for all subsequent development. Concomitantly, epiblast cells transit through distinct pluripotent states 3 , 4 , before lineage commitment at gastrulation. These pluripotent states have been characterized at the molecular level 5 , 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 that results in expression of glycosylated sialomucin proteins and the vesicle tethering and fusion events of lumenogenesis. Similarly, exit of epiblasts from naive pluripotency in cultured human post-implantation embryos 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.