Moreover, synthetic genetic programs, in which distinct cell–cell contacts specify differential cadherin expression, can induce self-organization into multidomain structures and sequential assembly 9. Cells expressing different types and levels of cadherins show differential cell–cell adhesion and sorting 1, 5, 6, 7, 8. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.Ĭadherins and protocadherins regulate cell adhesion forces in many different systems 1, 2, 3, 4. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast.

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