Pluripotent stem cell-derived organoids provide in vitro models of development and disease that can be used for a wide range of biomedical applications, including high-throughput screens or regenerative medicine. The ability of stem cells to self-renew and self-organize in three dimensions is the basis for creating highly structured multicellular organoid models. However, progress in clinical translation of organoid technologies has been stymied by the stochastic nature of stem cell differentiation within organoids, which leads to inconsistent cell type maturity, tissue function, reproducibility, and control over macroscale structure and phenotype(s). Advances in our understanding of developmental biology and the mechanisms which regulate symmetry breaking and pattern formation in the embryo have led to new approaches for engineering cooperative emergence (co-emergence) in organoid models to address these challenges.
In embryonic development, symmetry breaking events and the mechanical milieus in which they occur coordinate the specification of separate cell lineages. Here, we use 3D aggregates of human pluripotent stem cells (hPSCs) encapsulated in alginate microbeads to model the early blastocyst prior to zona pellucida hatching. We demonstrate that 3D confinement combined with modulation of cell-cell adhesions is sufficient to drive differentiation and collective migration reminiscent of the pre-implantation embryo. Knockdown of the cell adhesion protein CDH1 in encapsulated hPSC aggregates resulted in protrusion morphologies and emergence of extra-embryonic lineages, whereas unencapsulated CDH1(-) aggregates displayed organized radial delamination and mesendoderm specification bias. Transcriptomic similarities between single-cell RNA-sequencing data of early human embryos and encapsulated CDH1(-) aggregates establishes this in vitro system as a competent surrogate for studying early embryonic fate decisions and highlights the relationship between cell-cell adhesions and the mechanical microenvironment in directing cell fate and behavior.
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