Hypoblast from human pluripotent stem cells regulates epiblast development

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 () and Yasuhiro Takashima ()
Additional contact information
Takumi Okubo: Kyoto University
Nicolas Rivron: Vienna BioCenter (VBC)
Mio Kabata: Kyoto University
Hideki Masaki: University of Tokyo
Keiko Kishimoto: Central Institute for Experimental Animals
Katsunori Semi: Kyoto University
May Nakajima-Koyama: Kyoto University
Haruko Kunitomi: Kyoto University
Belinda Kaswandy: Kyoto University
Hideyuki Sato: University of Tokyo
Hiromitsu Nakauchi: University of Tokyo
Knut Woltjen: Kyoto University
Mitinori Saitou: Kyoto University
Erika Sasaki: Central Institute for Experimental Animals
Takuya Yamamoto: Kyoto University
Yasuhiro Takashima: Kyoto University

Nature, 2024, vol. 626, issue 7998, 357-366

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-023-06871-2

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