One week after fertilization, human embryos implant into the uterus. This event requires the embryo to form a blastocyst consisting of a sphere encircling a cavity lodging the embryo proper. Stem cells can form a blastocyst model that we called a blastoid1. Here we show that naive human pluripotent stem cells cultured in PXGL medium2 and triply inhibited for the Hippo, TGF-β and ERK pathways efficiently (with more than 70% efficiency) form blastoids generating blastocyst-stage analogues of the three founding lineages (more than 97% trophectoderm, epiblast and primitive endoderm) according to the sequence and timing of blastocyst development. Blastoids spontaneously form the first axis, and we observe that the epiblast induces the local maturation of the polar trophectoderm, thereby endowing blastoids with the capacity to directionally attach to hormonally stimulated endometrial cells, as during implantation. Thus, we propose that such a human blastoid is a faithful, scalable and ethical model for investigating human implantation and development3,4.
Current understanding of cell specification in early mammalian preimplantation development is mainly based on mouse studies. The first lineage differentiation event occurs at the morula stage with outer cells initiating a trophectoderm (TE) program to become the earliest placental progenitors. At subsequent developmental stages, the inner cell mass (ICM) arises from inner cells and is comprised of precursor cells of the embryo proper and yolk sac 1 . Notably, recent gene expression analyses suggest that the mechanisms regulating early lineage specification in the mouse may differ in other mammals, including human 2-5 and cow 6,7 . Here, we examined evolutionary conservation of cell dynamics and a molecular cascade initiating TE segregation in mouse, cow and human embryos using a comparative embryology approach. We discovered that the expression pattern of key TE lineage-associated factors shows a high degree of conservation among all three species. Specifically, at the morula stage outer cells acquire an apico-basal cell polarity, with expression of aPKC and PARD6B at the surface-free domain, nuclear expression of the Hippo signaling pathway effectors, YAP1 and WWTR1, and restricted expression of the transcription factor GATA3, suggesting initiation of a TE program. Furthermore, we demonstrate that inhibition of aPKC, by small-molecule pharmacological modulation and TRIM-Away protein depletion, impairs TE initiation at the morula stage. Altogether, our comparative embryology analysis provides novel insights into early lineage specification in human preimplantation embryos and suggests a similar mechanism initiating a TE program in mouse, cow and human embryos. Main textOur current understanding of cell specification during mammalian preimplantation development mainly relies on mouse studies. At the 8-cell stage, the mouse embryo undergoes a drastic
Integrated pseudotime analysis of human preimplantation embryo single-cell transcriptomes reveals the dynamics of lineage specification Graphical abstract Highlights d Distinct trophectoderm/epiblast signatures arise at the B2-B3 blastocyst stages d IFI16 is broadly expressed in the ICM and then restricted to epiblast after implantation d NR2F2 arises from the polar TE in late blastocysts and then spreads to all TE cells
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