Dynamic coupling of cell fate specification and cell sorting during mouse preimplantation development

During preimplantation development in mice, cells of the inner cell mass undergo a cell fate decision to become either Epiblast (Epi) or Primitive Endoderm (PrE) cells. Cell fate patterns during this stage range from an alternating pattern at the beginning to the separation of Epi and PrE at the end. Several mechanisms guiding this decision and pattern formation have been proposed, including intra- and intercellular signalling, cell division and cell sorting. The current understanding is that signalling generates the cell fates and subsequent sorting introduces the spatial cell fate separation. We used agent-based modelling to investigate whether cell differentiation and cell sorting can act concurrently and how their relative contributions to pattern formation may change over time. Comparing our model to experimental data for mouse blastocysts and ICM organoids, we find two mechanistic regimes that can produce the experimentally observed spatial separation: (i) simultaneous long-range intercellular signalling and cell sorting, and (ii) a gradual transition from short-range signalling to cell sorting, in which the timing is mediated via reducing cell fate plasticity. While the second agrees better with existing experimental evidence for late blastocysts, the first might still be relevant for early and mid blastocysts. Together, our results refine the sequential view of Epi/PrE patterning by showing that fate specification and cell sorting can be dynamically coupled, with their relative contributions changing over the course of blastocyst development.