Investigating the Mechanism of Cell Competition in mESCs

Abstract

Cell competition is a type of cell-cell interaction first described in Drosophila by Morato and Ripoll (1976), whereupon the co-existence of two cell populations with different metabolic properties or growth rates results in the growth of the stronger population at the expensive of the weaker one. BMP2 and 4 are the Drosophila homologues of Decapentaplegic which has been shown to have roles in cell competition. Based on data from studies on Drosophila models of cell competition, the lab generated mESCs null for Bmpr1a and investigated their behaviour when co-cultured with wild-type mESCs as a mammalian model of cell competition. This report further investigates changes in proliferation and apoptosis among competing cells and begins to investigate the signalling pathways which drive loser cells to initiate apoptosis. We report that apoptosis is caspase-dependent and possibly mediated by ERK and Wnt signalling as modulating these pathways changes the dynamics of competing cells. The report utilises a transwell growth system to demonstrate that cell competition is mediated by unknown signalling factors, an observation which has also been described in models of competing cells in Drosophila. The report shows that differentiation of mESCs is an important inducing factor for cell competition as naïve mESCs do not compete. Lastly this study shows that cell competition is a general mechanism of maintaining stem cell quality as other mutations which incur a growth or metabolic disadvantage as mESCs with defects in autophagy or are tetraploid are also eliminated by cell competition when co-cultured with wild-type cells.