Cell competition involves a conserved fitness-sensing process during which fitter cells eliminate neighbouring less-fit but viable cells¹. Cell competition has been proposed as a surveillance mechanism to ensure normal development and tissue homeostasis, and has also been suggested to act as a barrier to interspecies chimerism². However, cell competition has not been studied in an interspecies context during early development owing to the lack of an in vitro model. Here we developed an interspecies pluripotent stem cell (PSC) co-culture strategy and uncovered a previously unknown mode of cell competition between species. Interspecies competition between PSCs occurred in primed but not naive pluripotent cells, and between evolutionarily distant species. By comparative transcriptome analysis, we found that genes related to the NF-κB signalling pathway, among others, were upregulated in less-fit ‘loser’ human cells. Genetic inactivation of a core component (P65, also known as RELA) and an upstream regulator (MYD88) of the NF-κB complex in human cells could overcome the competition between human and mouse PSCs, thereby improving the survival and chimerism of human cells in early mouse embryos. These insights into cell competition pave the way for the study of evolutionarily conserved mechanisms that underlie competitive cell interactions during early mammalian development. Suppression of interspecies PSC competition may facilitate the generation of human tissues in animals.

细胞竞争涉及一个保守的适应度感知过程，在此过程中，适应度较高的细胞会淘汰邻近的适应度较低但存活的细胞¹。细胞竞争已被提议作为一种监视机制，以确保正常发育和组织稳态，并且还被提议作为种间嵌合的障碍²。然而，由于缺乏体外模型，早期发育过程中的细胞竞争尚未在种间背景下进行研究。在这里，我们开发了一种种间多能干细胞（PSC）共培养策略，并揭示了一种以前未知的物种间细胞竞争模式。PSC 之间的种间竞争发生在已启动但未幼稚的多能细胞中，以及进化上距离较远的物种之间。通过比较转录组分析，我们发现与 NF-κB 信号通路相关的基因等在不太适应的“失败者”人类细胞中表达上调。人类细胞中NF-κB复合物的核心成分（P65，也称为RELA）和上游调节因子（MYD88 ）的基因失活可以克服人类和小鼠PSC之间的竞争，从而改善人类细胞在细胞中的存活和嵌合状态。早期小鼠胚胎。这些对细胞竞争的见解为研究早期哺乳动物发育过程中竞争性细胞相互作用的进化保守机制铺平了道路。抑制种间 PSC 竞争可能会促进动物体内人体组织的产生。