Competitive Interactions Eliminate Unfit Embryonic Stem Cells at the Onset of Differentiation

A fundamental question in developmental biology is whether there are mechanisms to detect stem cells with mutations that, although not adversely affecting viability, would compromise their ability to contribute to further development. Here, we show that cell competition is a mechanism regulating the fitness of embryonic stem cells (ESCs). We find that ESCs displaying defective bone morphogenetic protein signaling or defective autophagy or that are tetraploid are eliminated at the onset of differentiation by wild-type cells. This elimination occurs in an apoptosis-dependent manner and is mediated by secreted factors. Furthermore, during this process, we find that establishment of differential c-Myc levels is critical and that c-Myc overexpression is sufficient to induce competitive behavior in ESCs. Cell competition is, therefore, a process that allows recognition and elimination of defective cells during the early stages of development and is likely to play important roles in tissue homeostasis and stem cell maintenance. [Display omitted] •Defective ESCs are eliminated at the onset of differentiation by wild-type cells•Elimination of unfit cells is apoptosis dependent and mediated by secreted factors•Higher c-Myc levels are established in wild-type ESCs cocultured with unfit cells•c-Myc overexpression induces a competitive advantage in ESCs Sancho et al. show that embryonic stem cells undergo cell competition to recognize and eliminate defective neighbors at the onset of differentiation. Cell competition, driven by differential c-Myc expression, provides a mechanism to monitor the fitness of pluripotent stem cells during early mammalian embryogenesis.