MYCN-Driven Cell Competition Provokes Interspecies Chimerism Using Human Pluripotent Stem Cells

Human pluripotent stem cells (hPSCs) exhibit very low efficiency in interspecies chimeras due to cell-autonomous apoptosis, but the underlying mechanism remains unclear. Here, we reveal that the cell death of hPSCs is due to a loser fate in competition with mouse PSCs (mPSCs) when they differentiate together. While, forced-expression of MYCN overcomes the competition failure of hPSCs and greatly enhances their survival rate from 0.5% to 75% in teratoma formation mixed with mPSCs in 1:1 ratio. MYCN combined with BCL2 (M/B) provokes the robust integration of primed hPSCs into pre-implantation embryos of different species such as mouse, rabbit and pig. Furthermore, M/B-hPSCs injected in pre-implantation embryos differentiate with the progress of development and generate human endothelial and blood cells in Flk-1 deficient mouse embryos through complementation. Together, our findings reveal the competition failure is an important barrier in interspecies chimerism using hPSCs and provide a way to overcome it.