Hypoblast from human pluripotent stem cells regulates epiblast development

• 成果类型: Article
• 署名作者: Okubo, Takumi; Rivron, Nicolas; Kabata, Mio; Masaki, Hideki; Kishimoto, Keiko; Semi, Katsunori; Nakajima-Koyama, May; Kunitomi, Haruko; Kaswandy, Belinda; Sato, Hideyuki; Nakauchi, Hiromitsu; Woltjen, Knut; Saitou, Mitinori; Sasaki, Erika; Yamamoto, Takuya; Takashima, Yasuhiro
• 署名单位: Kyoto University; Austrian Academy of Sciences; Vienna Biocenter (VBC); Institute of Molecular Biotechnology (IMBA); University of Tokyo; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); Stanford University; Kyoto University; Kyoto University; RIKEN
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3972
• DOI: 10.1038/s41586-023-06871-2
• 发表日期: 2024-02-08
• 关键词: primitive endoderm; self-organization; mouse; lineage; differentiation; conversion; induction; embryo; fate; morphogenesis

摘要

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. Authentic hypoblast cells created from naive human pluripotent stem cells (hPSCs) spontaneously assemble with naive hPSCs to form a three-dimensional bilaminar structure (bilaminoids) with a pro-amniotic-like cavity.