Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation

Abstract

During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality control mechanism that contributes to this balance by eliminating viable cells that are less-fit than their neighbours. What mutations confer cells with a competitive advantage or the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are super-competitors that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependant, as does not occur when cells are pluripotent and is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through a competition for space or nutrients, but instead is mediated by short range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development.

P53 and BCL-2 family proteins PUMA and NOXA define competitive fitness in pluripotent cell competition

“…In some studies it was reported that in naive conditions p53 -/- cells behave as losers instead of winners [ 41 ]. In agreement with Montero and colleagues [ 23 ], we found that in 2i conditions, p53 -/- cells do not show any competitive advantage or disadvantage with respect to WT cells ( Fig 7P ). Interestingly, in naive conditions, WT and p53 -/- ESCs show a similar and small proportion of cells with activated Caspase 3 ( Fig 7Q ) and showed no differences in mitotic index ( Fig 7R ).…”

“…Previous reports showed that CC driven by different pathways does not take place in naive pluripotent cells [ 5 , 20 , 23 ]. In some studies it was reported that in naive conditions p53 -/- cells behave as losers instead of winners [ 41 ].…”

“…Similar observations apply to the in vitro counterparts of epiblast cells as they transit from naive to primed pluripotency and differentiation ( S1 Fig ). Although different pathways have been reported to regulate fitness in pluripotent CC [ 4 , 5 , 20 – 23 ], many aspects of the molecular mechanisms involved remain unknown. In particular, how competitive fitness is encoded in pluripotent cells is not understood.…”

Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells

“…Additionally, cell competition is primarily dependent on short-range interactions between neighbors 36,42,47 , and our data suggest this is the same for Myc-and p53-mediated competitive interactions between aneuploid and diploid hESCs. But it is unknown how relative differences in cell fitness are communicated between neighbors to affect their fate.…”

Quantitative Experimental Embryology: A Modern Classical Approach

“…When these cells are injected into the early mouse embryo to create a chimera, they show enhanced competitive abilities and are not eliminated from the population. The mTOR pathway, responsible for aspects of cell competition, was shown to be under the control of p53 in this context, and the removal of p53 activity is able to create ‘super-competitor’ cells [ 29 , 30 ]. Similarly, cMyc protein levels correlate with competitiveness, and over-expression is able to direct the elimination of otherwise healthy cells from the population [ 31 ].…”