Cell competition between human and mouse primed PSCs

Cell competition entails an evolutionarily conserved fitness-sensing process during which fitter cells eliminate their neighboring less-fit but otherwise viable cells. Cell competition has been proposed as a surveillance mechanism to ensure normal development and maintain tissue homeostasis, and also been suggested to act as a barrier to interspecies chimerism. To date, however, cell competition has not been examined in an interspecies context during early development due to lack of in vitro model. Here, we develop an interspecies pluripotent stem cell (PSC) co-culture strategy and uncover a previously unknown mode of cell competition. Interspecies PSC competition occurs during primed but not naive pluripotency, and between evolutionarily distant species. We identified genes related to P53 and NF-κB signaling pathways, among others, were upregulated in loser cells and genetic inactivation of either TP53 or RELA, a core component of canonical NF-κB pathway, could overcome interspecies PSC competition. We further showed that MYD88 innate immune signal transduction adaptor was also involved in promoting loser PSC elimination. Suppressing interspecies PSC competition via genetic perturbation of MYD88, P65, or TP53 improved engraftment of human cells in early post-implantation mouse embryos. Our study discovers a new paradigm of cell competition and paves the way for studying evolutionarily conserved cell competition mechanisms during early mammalian development. Strategies developed here to overcome interspecies PSC competition may facilitate the xeno-generation of human tissues in animals.