2CLCs emerge most often from naive ES cells, but downregulate protein levels of pluripotency factors 10. In addition, 2CLCs recapitulate other features of 2-cell embryos including their chromatin accessibility landscape 9, greater global histone mobility 13 and the capacity to contribute to extra-embryonic tissues 8.Īlthough not strictly totipotent, 2CLCs are considered totipotent-like cells and are therefore a powerful cellular model to study molecular features related to totipotency. This includes the transcription factor ZSCAN4 11 and retrotransposons from the MERVL family 12. 2CLCs share several features with 2-cell stage embryos, including a ‘2 C’ transcriptional program, characterized by genes expressed upon zygotic genome activation (ZGA), which occurs in late 2-cell embryos 8, 9, 10.
Among these, cells resembling the blastomeres of 2-cell stage embryos, referred to as ‘2-cell-like-cells’ (2CLCs), arise spontaneously, constituting less than 1% of the cells 8. Depending on the culture conditions, ES cell cultures can be highly heterogeneous, in which distinct cell populations with diverse developmental potentials coexist. The establishment of ES cell lines over 30 years ago 7 has enabled their use as model system to study pluripotency. Pluripotent embryonic stem (ES) cells derive from the ICM. In contrast to totipotent cells, pluripotent cells can no longer contribute to the extra-embryonic derivatives of the trophectoderm 6. Three days after fertilization, the blastocyst forms and pluripotent cells emerge within the inner cell mass (ICM) 2.
As development progresses, totipotency is lost and cellular plasticity is gradually reduced.
#Arrested development since the last time rar full#
Totipotency is a transient feature of the cells in the early embryo, which in mice is limited to the zygote and 2-cell embryo, because only the blastomeres of these stages can autonomously generate a full organism 3, 4, 5. Totipotency is the ability of a cell to give rise to a full organism 1, 2 and encompasses the broadest cellular plasticity in the mammalian body. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos.
Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. Such ‘2-cell-like-cells’ (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Totipotent cells hold enormous potential for regenerative medicine.
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