Early developmental plasticity enables the induction of an intermediate extraembryonic cell state

Abstract

Two fundamental elements of pre-implantation embryogenesis are cells’ intrinsic self-organization program and their developmental plasticity, which allows embryos to compensate for alterations in cell position and number; yet, these elements are still poorly understood. To be able to decipher these features, we established culture conditions that enable the two fates of blastocysts’ extraembryonic lineages—the primitive endoderm and the trophectoderm—to coexist. This plasticity emerges following the mechanisms of the first lineage segregation in the mouse embryo, and it manifests as an extended potential for extraembryonic chimerism during the pre-implantation embryogenesis. Moreover, this shared state enables robust assembly into higher-order blastocyst-like structures, thus combining both the cell fate plasticity and self-organization features of the early extraembryonic lineages.

Enhancer status in the primitive endoderm supports unrestricted lineage plasticity in regulative development

“…While these endodermal reprogramming intermediates were initially reminiscent of nEnd, our analysis of transcriptomic data demonstrates that these XEN-like intermediates resemble postimplantation-stage endoderm or XEN cells and that subpopulations of nEnd fall along the trajectory to acquisition of pluripotency. Moreover, our data suggests that the transition between DP and Oct4 + nEnd does not occur through reprogramming via a 2C-like intermediate, but rather as a direct conversion between lineages, in agreement with recent reports 45,87 .…”

“…While our observations regarding the potential of nEnd to initiate TE specification were inconclusive, a recent study found TSCs could be derived from an extra-embryonic endoderm-like intermediate 45 . We therefore asked whether nEnd could differentiate into TSCs in vitro.…”

The primitive endoderm supports lineage plasticity to enable regulative development

“…As TSCs have previously been derived from an extra-embryonic endoderm-like intermediate, 63 we asked whether nEnd could differentiate into TSCs in vitro . PDGFRA-APC single positive nEnd were differentiated in TSC medium 33 for 7 days.…”

“…Moreover, our data suggest that the transition between DP and Oct4 + nEnd does not occur via a 2C-like intermediate but rather as a direct conversion between lineages. 63 , 112 …”

The role of lipids in genome integrity and pluripotency

“…ESCs were initially derived from ICM cells in blastocyst stage, which can differentiate into all cell types in an adult body. While it was believed that they lost bipotentiality, recent reports have shown that ICM cells retain their bipotential nature until the second lineage specification [ 71 , 72 ].…”