Hypoblast from human pluripotent stem cells regulates epiblast development.

Nature 2024 Feb

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Recently, several studies using cultures of human embryos together with single-cell RNA-seq analyses have revealed differences between humans and mice, necessitating the study of human embryos1-8. Despite the importance of human embryology, ethical and legal restrictions have limited post-implantation-stage studies. Thus, recent efforts have focused on developing in vitro self-organizing models using human stem cells9-17. Here, we report genetic and non-genetic approaches to generate authentic hypoblast cells (naive hPSC-derived hypoblast-like cells (nHyCs))-known to give rise to one of the two extraembryonic tissues essential for embryonic development-from naive human pluripotent stem cells (hPSCs). Our nHyCs spontaneously assemble with naive hPSCs to form a three-dimensional bilaminar structure (bilaminoids) with a pro-amniotic-like cavity. In the presence of additional naive hPSC-derived analogues of the second extraembryonic tissue, the trophectoderm, the efficiency of bilaminoid formation increases from 20% to 40%, and the epiblast within the bilaminoids continues to develop in response to trophectoderm-secreted IL-6. Furthermore, we show that bilaminoids robustly recapitulate the patterning of the anterior-posterior axis and the formation of cells reflecting the pregastrula stage, the emergence of which can be shaped by genetically manipulating the DKK1/OTX2 hypoblast-like domain. We have therefore successfully modelled and identified the mechanisms by which the two extraembryonic tissues efficiently guide the stage-specific growth and progression of the epiblast as it establishes the post-implantation landmarks of human embryogenesis. © 2023. The Author(s).

Citation

Takumi Okubo, Nicolas Rivron, Mio Kabata, Hideki Masaki, Keiko Kishimoto, Katsunori Semi, May Nakajima-Koyama, Haruko Kunitomi, Belinda Kaswandy, Hideyuki Sato, Hiromitsu Nakauchi, Knut Woltjen, Mitinori Saitou, Erika Sasaki, Takuya Yamamoto, Yasuhiro Takashima. Hypoblast from human pluripotent stem cells regulates epiblast development. Nature. 2024 Feb;626(7998):357-366