P53 and PUMA in Pluripotent Cell Competition

Abstract

Cell Competition (CC) is a biological process in which viable cells are eliminated by the presence of neighbouring cells with increased fitness. First observed in Drosophila, Cell Competition has been described in numerous biological scenarios in metazoans both du¬ring embryonic development and in the adult. Cell Competition has been envisioned as a conserved and extended quality control system that eliminates less fit, mispatterned or non-well adapted cells, ensuring homeostasis and proper function of tissues and organs throughout life. During the early mouse development, the mouse epiblast and its in vitro counterpart, mouse embryonic stem cells (ESCs) are subjected to natural Cell Competition. Through this mechanism, suboptimal or potentially harmful cells are removed by the presence of fitter cells, optimizing the pool of cells that will give rise to the new individual. This endogenous CC model correlates with MYC transcription factor expression, so cells with low MYC levels are eliminated by the presence of cells with higher levels (Clavería et al., 2013; Díaz-Díaz et al., 2017; Sancho et al., 2013). This process relies on the interaction and comparison between cells with different fitness, which results in the elimination of less fit cells. However, these molecular mechanisms remain largely unknown, especially in mammals. Here, we have explored different factors and pathways regulating cell fitness and the execution of loser cell death. We have identified and analysed different candidates of the P53 pathway and propose a model based on increased susceptibility to apoptosis, autophagy and mitophagy induction and reduction of mitochondrial OXPHOS function, accounting, at least in part, for the loser “signature” in pluripotent Cell Competition. We have found that P53 and PUMA regulate apoptosis susceptibility in ESCs but their function and expression is not restricted to apoptotic cells. We have shown that P53 activity inhibits MYC expression and is strictly required for PUMA expression. P53 and PUMA regulate fitness and induces Cell Competition in ESCs. P53 regulation of competitive fitness depends on the pluripotency status, with the pathway being activated as the cells progress towards differentiation and their ability to induce Cell Competition is supressed in naïve pluripotency conditions. We propose a model that integrates the P53 pathway and MYC in the definition of the lo¬ser cell fitness “status” and suggests that an alteration in mitochondrial OXPHOS function regulated by P53-PUMA underlies competitive fitness in pluripotent cells.