The embryo game uncovers hidden cell behaviours for viability

Abstract To succeed, the embryo depends on the underlying behaviours of its individual cells. While cells are naturally driven to preserve their own survival, they must work together to ensure embryo viability. Herein lies a dilemma: the action of each cell can elicit a reaction that benefits the collective at a cost to itself. To explore how cell behaviours drive embryo success, we intersect evolutionary game theory and in vitro embryo modelling to simulate how cell interactions impact viability. We consider cell competition, a form of cell killing observed in embryonic development across species, thought to enable error correction. However, few studies have directly linked cell killing to embryo success. Our collective risk game shows that while killing is costly for the individual cell, it is beneficial when the embryo exceeds a viable target size and the probability of survival is low. In heX-embryoids, inhibiting cell death leads to larger structures and higher failure frequency. Successful single lumen embryoids form within the size range of the native human embryonic disc (the target size). Further, we find that killing and proliferating are responsive cellular behaviours used to maintain optimal embryoid size and viability, consistent with their emergence as conditional strategies in our game. Finally, our game predicts that conditional killing may be a “threat” used to protect against over-proliferating cells, compelling them to follow the rules by adding their fair share of progeny to the embryo. Our results provide insights into the emergence of killing as a useful, responsive strategy for embryo viability. Counter-intuitively, this suggests that competition underpins cooperation amongst cells for embryonic success. Our dual computational and engineered embryo modelling approach sheds light into the black box of human development while providing an opportunity to monitor embryo health by leveraging hidden cell interactions.