TY - JOUR
T1 - Cell competition constitutes a barrier for interspecies chimerism
AU - Zheng, Canbin
AU - Hu, Yingying
AU - Sakurai, Masahiro
AU - Pinzon-Arteaga, Carlos A.
AU - Li, Jie
AU - Wei, Yulei
AU - Okamura, Daiji
AU - Ravaux, Benjamin
AU - Barlow, Haley Rose
AU - Yu, Leqian
AU - Sun, Hai Xi
AU - Chen, Elizabeth H.
AU - Gu, Ying
AU - Wu, Jun
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/4/8
Y1 - 2021/4/8
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85099911814&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03273-0
DO - 10.1038/s41586-021-03273-0
M3 - Article
C2 - 33508854
AN - SCOPUS:85099911814
SN - 0028-0836
VL - 592
SP - 272
EP - 276
JO - Nature
JF - Nature
IS - 7853
ER -