Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Abstract

Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated prior to gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single cell transcriptional profiling of eliminated mouse epiblast cells we identify hallmarks of cell competition and mitochondrial defects. We go on to demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. In the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.

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

“…One important implication of cell competition is that the fitness of a cell is relative to the fitness of its neighbour. For example, in mouse, wild-type cells eliminate cells with mitochondrial dysfunction (Lima et al, 2021), but are eliminated by cells that over-express c-MYC (Claveria et al, 2013; Sancho et al, 2013). Here, we have addressed how the expression levels of P53 affects the competitive nature of pluripotent cells.…”

“…In the post-implantation embryo, just prior to gastrulation, this process eliminates around 35% of embryonic cells due to repression of the mTOR pathway (Bowling et al, 2018). This large-scale elimination is thought to ensure that only the fittest cells go on to contribute to further development and the germline (Bowling et al, 2019), and one important trigger of this elimination is mitochondrial dysfunction and mitochondrial DNA mutations (Lima et al, 2021). In the pre-implantation mouse embryo signalling via the Hippo pathway is required for the elimination through cell competition of mis-patterned cells (Hashimoto and Sasaki, 2019) and this pathway also mediates the elimination of normal human embryonic stem cells (ESCs) by karyotypically abnormal ones (Price et al, 2021), explaining how the abnormal cells expand in human pluripotent stem cell cultures.…”

“…Importantly, the cells eliminated in the early post-implantation mouse embryo display elevated P53 levels (Bowling et al, 2018; Lima et al, 2021) and cells with increased P53 expression are also eliminated during mouse during organogenesis (Zhang et al, 2017). In Madin-Darby Canine Kidney (MDCK) cells, mutation of the cell polarity gene Scribble in a mosaic fashion leads to an increase in P53 that induces mutant cell elimination via mechanical cell competition (Wagstaff et al, 2016).…”

The Field of Cell Competition Comes of Age: Semantics and Technological Synergy

“…The use of the term “fitness” is a clear example of this. In the context of CC, “fitness” is widely used to describe the inherent qualities of winner cells that confer their ability to eliminate losers ( Clavería et al, 2013 ; Sancho et al, 2013 ; Bowling et al, 2019 ; Madan et al, 2019 ; Lima et al, 2021 ). However, the ability to eliminate losers is often defined by the cell’s “fitness”; an argument that begins where it ends.…”

“…“Scramble” involves a rush to accumulate a limited number of resources, whereas “contests” involve direct interactions, comparisons, or sensing between competing cell populations. (A) Examples of “costly contests” include direct apoptotic induction of loser cells by winners as seen in mouse embryonic stem cell models ( Díaz-Díaz et al, 2017 ; Bowling et al, 2018b ; Lima et al, 2021 ), or via extrusion of losers from the underlying substrate by neighbours as seen in tissue culture models ( Hogan et al, 2009 ; Kajita et al, 2010 ). (B) “Costly scrambles” have been seen in intestinal stem cell models, where apc -mutant cells with constitutive WNT signaling secrete a WNT antagonist, NOTUM, crippling WNT signaling in their wildtype neighbours and limiting their ability to persist in the stem cell state ( Flanagan et al, 2021 ; Scheuer et al, 2021 ).…”