Chemical reversion of mouse post-implantation epiblast directly to totipotent-like cells

Totipotent cells can give rise to all cell types in an organism. Mouse totipotent-like cells (TLCs) have been generated from undifferentiated pluripotent embryonic stem cells (ESCs). However, it remains unknown whether TLCs can be generated from differentiated cells. Here, we report a novel chemically defined medium which can efficiently induce TLCs from differentiation-committed cells including epiblast-like cells (EpiLCs) and post-implantation epiblast. Comparatively, MERVL-GFP positive cells induced from differentiated cells exhibit closer transcriptome characteristics to 2-cell (2C) embryos in contrast to those induced from pluripotent ESCs. Moreover, differentiated cells exhibit distinct reprogramming kinetics and pathways to TLCs compared to ESCs. They are directly and rapidly reprogrammed into TLCs without passing through a pluripotent intermediate. Notably, TLCs were generated from post-implantation epiblast and demonstrated the capacity to contribute to both embryonic and extra-embryonic lineages in chimeras. Overall, these findings have significant implications for understanding the mechanism of totipotency acquisition and cell plasticity.