MYCN-Driven Cell Competition Provokes Interspecies Chimerism Using Human Pluripotent Stem Cells
Social Science Research Network(2020)
摘要
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.
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