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

Abstract

SummaryA 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.

Competition between human cells by entosis

“…While the identity of the engulfing cells and whether engulfment itself mediates competition in Drosophila are controversial, we clearly show that neighboring cell-mediated engulfment and killing occur in mixed populations of human cells. Other mechanisms of competition between mammalian cells have been demonstrated, including the differential extrusion of cells of mixed genotypes from monolayer cultures [9,10], competition between cells of the early embryo [36][37][38], and competition between hematopoietic progenitors driven by differences in p53 activity [39,40]. Perhaps diverse competition mechanisms reflect a stringent requirement for homeostasis in different contexts within various tissue types of metazoan organisms during development and adulthood.…”

Cell competition, apoptosis and tumour development

“…More recently, two studies (Claveria et al, 2013, Sancho et al, 2013 have shown that cell competition has a functional role during early mouse development. At the epiblast stage there is endogenous cell competition so that cells with lower levels of Myc are eliminated (Claveria et al, 2013).…”

Differential DNA damage signalling and apoptotic threshold correlate with mouse epiblast-specific hypersensitivity to radiation

“…It is noteworthy that this low apoptotic threshold might play an equally important role in other types of stresses, such as those associated with a lack of nutrients or growth factors, or Myc-driven cell competition (Clavería et al, 2013;Sancho et al, 2013). Thus, because of the high level of vigilance of Epi cells at the E5.5-6.5 transition, it is not surprising that so many mouse mutants are lethal at this specific stage, a representative example being Mdm2 −/− (Jones et al, 1995): the depletion of this p53 inhibitor induces apoptosis after E5.5 in Epi cells, which we now show concomitantly express consistent levels of p53 and are very close to crossing the apoptotic threshold.…”