Cell competition constitutes a barrier for interspecies chimerism
Cell competition constitutes a barrier for interspecies chimerism
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DOI：
10.1038/s41586-021-03273-0
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发表时间：
2021-01-28
期刊：
影响因子：
64.8
通讯作者：
Wu, Jun
中科院分区：
文献类型：
--
作者：
Zheng, Canbin;Hu, Yingying;Wu, Jun
细胞竞争涉及一个保守的适应性感知过程，在此过程中，适应性较强的细胞会消除相邻的适应性较差但有活力的细胞（1）。细胞竞争被认为是一种监督机制，以确保正常发育和组织稳态，也被认为是种间嵌合的障碍（2）。然而，由于缺乏体外模型，在早期发育过程中，细胞竞争尚未在种间背景下进行研究。在这里，我们开发了一种跨物种多能干细胞（PSC）共培养策略，并发现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引发的多能细胞中，而不是幼稚的多能细胞，以及进化上遥远的物种之间。通过比较转录组分析，我们发现与NF-κ B信号通路相关的基因在不太适合的“失败者”人类细胞中上调。人细胞中NF-κ B B复合物的核心组分（P65，也称为RELA）和上游调节因子（MYD 88）的基因失活可以克服人和小鼠PSC之间的竞争，从而改善早期小鼠胚胎中人细胞的存活和嵌合状态。这些见解细胞竞争铺平了道路的进化保守的机制，在早期哺乳动物发育过程中的竞争性细胞相互作用的研究。种间PSC竞争的抑制可促进动物中人类组织的产生。
Cell competition involves a conserved fitness-sensing process during which fitter cells eliminate neighbouring less-fit but viable cells(1). 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 chimerism(2). 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-kappa B 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-kappa B 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.