Cell competition constitutes a barrier for interspecies chimerism.

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Cellular Mechanisms

Background:

• Cell competition is a conserved process where fitter cells eliminate less-fit neighbors, crucial for development and homeostasis.
• It's proposed as a barrier to interspecies chimerism, but an in vitro model for early development was lacking.

Purpose of the Study:

• To develop an in vitro model for studying interspecies cell competition during early development.
• To uncover novel modes of cell competition between different species' pluripotent stem cells (PSCs).

Main Methods:

• Developed an interspecies pluripotent stem cell (PSC) co-culture strategy.
• Performed comparative transcriptome analysis of competing human and mouse PSCs.
• Genetically modified human cells by inactivating NF-κB pathway components (P65/RELA, MYD88).

Main Results:

• Discovered a new mode of interspecies PSC competition, occurring in primed but not naive pluripotent cells and between evolutionarily distant species.
• Identified upregulation of NF-κB signaling pathway genes in less-fit 'loser' human cells.
• Inactivating NF-κB components in human cells rescued competition, enhancing human cell survival and chimerism in early mouse embryos.

Conclusions:

• Interspecies cell competition is regulated by the NF-κB signaling pathway.
• Overcoming this competition may enable the generation of human tissues in animals.
• This work opens avenues for studying conserved competitive cell interactions in early mammalian development.