Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension

Abstract

Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. 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. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. 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. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.

Behind the developing brains and beating hearts of stem cell-derived embryo models

“…After 24 h, the assembled structure becomes fixed by an increase in cortical tension in all cell types, thereby decreasing cell mobility. A detailed discussion together with in silico modelling is given elsewhere [32]. Drawings by Andy Cox and Min Bao.…”

“…Three different cell types had been added to a well and a substantial portion of them could, through random collisions, self-assemble into the correct multicellular structures. Understanding of how this could be achieved has been recently described by Min Bao et al [32]. Two factors were found to be of major importance in the self-assembly of these ETX structures: cell adhesion and cortical tension.…”

“…Three different cell types had been added to a well and a substantial portion of them could, through random collisions, self-assemble into the correct multicellular structures. It is not only adhesion, but also cortical tension that influences the self-assembly process [32]. A decrease in the cortical tension of XEN cells is of particular importance early in the assembly process to achieve the externalization of the XEN cell layer.…”

“…It is not only adhesion, but also cortical tension that influences the self-assembly process [32]. A decrease in the cortical tension of XEN cells is of particular importance early in the assembly process to achieve the externalization of the XEN cell layer.…”

Morphogenesis and development of human telencephalic organoids in the absence and presence of exogenous ECM

“…The impact of endogenous and exogenous ECM sources on epithelial morphogenesis has been addressed in other in vitro systems. An example are experimental paradigms that show the formation of somites, for which either a low concentration of Matrigel in the culture medium ( Sanaki-Matsumiya et al ., 2022; van den Brink et al ., 2020; Veenvliet et al ., 2020) or differentiation of ECM-producing cells within the tissue are required ( Amadei et al ., 2022; Bao et al ., 2022; Lau et al ., 2022). Similarly, breast luminal epithelial cells can be polarized in vitro by exogenous addition of laminin-1, or co-culture with ECM-producing myoepithelial cells ( Gudjonsson et al ., 2002).…”