Cell competition constitutes a barrier for interspecies chimerism

Canbin Zheng, Yingying Hu, Masahiro Sakurai, Carlos A. Pinzon-Arteaga, Jie Li, Yulei Wei, Daiji Okamura, Benjamin Ravaux, Haley Rose Barlow, Leqian Yu, Hai-Xi Sun, Elizabeth H. Chen, Ying Gu and Jun Wu ()
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Canbin Zheng: Sun Yat-sen University
Yingying Hu: University of Texas Southwestern Medical Center
Masahiro Sakurai: University of Texas Southwestern Medical Center
Carlos A. Pinzon-Arteaga: University of Texas Southwestern Medical Center
Jie Li: BGI-Shenzhen
Yulei Wei: University of Texas Southwestern Medical Center
Daiji Okamura: Kindai University
Benjamin Ravaux: University of Texas Southwestern Medical Center
Haley Rose Barlow: University of Texas Southwestern Medical Center
Leqian Yu: University of Texas Southwestern Medical Center
Hai-Xi Sun: BGI-Shenzhen
Elizabeth H. Chen: University of Texas Southwestern Medical Center
Ying Gu: BGI-Shenzhen
Jun Wu: University of Texas Southwestern Medical Center

Nature, 2021, vol. 592, issue 7853, 272-276

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03273-0

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