From fitness to fate: Hippo-YAP-mediated cell competition influence on stem cells activity

Cell competition is a fundamental quality-control mechanism where fitter 'winner' cells eliminate less-fit 'loser' counterparts, thereby fine-tuning cell populations during development and maintaining adult tissue integrity. This highly conserved, natural cellular process is absolutely crucial for organogenesis, but once dysfunctional, can instead be exploited by 'super-fit' cancer cells to promote tumourigenesis. This review aims to provide an overview of how heterogeneity is the root cause of cell competition, the factors which influence its emergence, the various modes of cell competition, and finally, the mechanisms by which loser cells are eliminated. We are particularly interested in YAP, a major effector of the Hippo signalling cascade, as a driver of heterogeneity and perpetrator of human pluripotent stem cell (hPSCs) competition. We discuss how differential YAP/TEAD activity, influenced by mechanical stress, defines winner and loser cell identities within stem cell populations. Finally, we discuss the potential of cell competition for advancing regenerative medicine and cancer therapy.