Human naive epiblast cells possess unrestricted lineage potential.

Ayaka Yanagida,Meng Amy Li,Giuliano Giuseppe Stirparo,Daniel Spindlow,Stanley E Strawbridge,Buse Nurten Özel,Sam Myers,Jennifer Nichols,Ge Guo,Jian Yang,James Clarke,Anish Dattani,Austin Smith

doi:10.1016/j.stem.2021.02.025

Abstract

SummaryClassic embryological experiments have established that the early mouse embryo develops via sequential lineage bifurcations. The first segregated lineage is the trophectoderm, essential for blastocyst formation. Mouse naive epiblast and derivative embryonic stem cells are restricted accordingly from producing trophectoderm. Here we show, in contrast, that human naive embryonic stem cells readily make blastocyst trophectoderm and descendant trophoblast cell types. Trophectoderm was induced rapidly and efficiently by inhibition of ERK/mitogen-activated protein kinase (MAPK) and Nodal signaling. Transcriptome comparison with the human embryo substantiated direct formation of trophectoderm with subsequent differentiation into syncytiotrophoblast, cytotrophoblast, and downstream trophoblast stem cells. During pluripotency progression lineage potential switches from trophectoderm to amnion. Live-cell tracking revealed that epiblast cells in the human blastocyst are also able to produce trophectoderm. Thus, the paradigm of developmental specification coupled to lineage restriction does not apply to humans. Instead, epiblast plasticity and the potential for blastocyst regeneration are retained until implantation.

Highlights

Delamination of epithelial trophectoderm is the first differentiation event in mammalian embryos
We examined the fate of cultures treated with PD and A83 (PD+A83) for only 24 h and released into N2B27 for 3 days
We found that addition of bone morphogenetic protein (BMP) or the BMP receptor inhibitor LDN-193189 (LDN) had a negligible effect on induction of GATA3:mKO2 in PD+A83 (Figure S6A)

Summary

Introduction

Delamination of epithelial trophectoderm is the first differentiation event in mammalian embryos. Following fertilization and early cleavage divisions, blastomeres divide asymmetrically to form trophectoderm and inner cell mass (ICM). A second binary fate decision resolves the ICM into epiblast and hypoblast (primitive endoderm) (Chazaud et al, 2006; Gardner and Rossant, 1979; Plusa et al, 2008; Saiz et al, 2016). These observations have given rise to a textbook model of sequential lineage bifurcations at the onset of mammalian embryo development (Rossant, 2018)

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