# The primitive endoderm supports lineage plasticity to enable regulative development

## TL;DR

The primitive endoderm can regenerate a complete embryo on its own, showing unexpected developmental flexibility.

## Contribution

The study reveals that the primitive endoderm alone can form a blastocyst and sustain development, challenging its traditional role.

## Key findings

- Primitive endoderm can regenerate a complete blastocyst without other cell types.
- Naive extra-embryonic endoderm stem cells in vitro mimic this regenerative capacity.
- OCT4 and enhancer landscapes maintain plasticity in the primitive endoderm.

## Abstract

Mammalian blastocyst formation involves the specification of the trophectoderm followed by the differentiation of the inner cell mass into embryonic epiblast and extra-embryonic primitive endoderm (PrE). During this time, the embryo maintains a window of plasticity and can redirect its cellular fate when challenged experimentally. In this context, we found that the PrE alone was sufficient to regenerate a complete blastocyst and continue post-implantation development. We identify an in vitro population similar to the early PrE in vivo that exhibits the same embryonic and extra-embryonic potency and can form complete stem cell-based embryo models, termed blastoids. Commitment in the PrE is suppressed by JAK/STAT signaling, collaborating with OCT4 and the sustained expression of a subset of pluripotency-related transcription factors that safeguard an enhancer landscape permissive for multi-lineage differentiation. Our observations support the notion that transcription factor persistence underlies plasticity in regulative development and highlight the importance of the PrE in perturbed development.

•The primitive endoderm can form an embryo in the absence of any other cell types•Naive extra-embryonic endoderm (nEnd) stem cells recapitulate this capacity in vitro•OCT4 expression in the primitive endoderm sustains plasticity•The enhancer landscape in nEnd maintains plasticity for all preimplantation lineages

The primitive endoderm can form an embryo in the absence of any other cell types

Naive extra-embryonic endoderm (nEnd) stem cells recapitulate this capacity in vitro

OCT4 expression in the primitive endoderm sustains plasticity

The enhancer landscape in nEnd maintains plasticity for all preimplantation lineages

Although generally considered a simple support tissue, extra-embryonic primitive endoderm has the capacity to regenerate a complete blastocyst and continue post-implantation development.