The University of Hong Kong, China (People's Republic)
Abstract: Totipotent cells can give rise to all the cell lineages in both the embryonic and the extraembryonic tissues. In the mouse, the zygote and the blastomeres of the early 2-cell embryo are authentic totipotent cells. Despite the importance of totipotency in starting life, how totipotency is established from fusion of the two gametes and subsequently regulated remains fully understood. Derivation and maintenance of stem cells in vitro with totipotency features would offer an invaluable model for studying the molecular mechanism of totipotency. Here, we demonstrate that a single molecule, CBL0137, enables establishment and culturing of totipotent-like stem cells from pluripotent stem cells. These new stem cells generate both embryonic and extraembryonic cell lineages in in vitro differentiation, blastoid generation, and in vivo chimeras. We designate these cells as Z-cells (zygotic genome activation (ZGA)-like cells), which transcriptionally and epigenetically resemble 2-cell embryo cells. Remarkably, CBL0137 can also induce cells in the blastocyst and embryonic fibroblasts to acquire 2C embryo-like molecular features, indicating that CBL0137 re-establishes 2C-specific transcriptome in a lineage-independent manner. Furthermore, CBL0137 can induce MEFs to acquire molecular features of other cell lineages. The CBL0137-induced cell fate transition therefore provides an in vitro system to efficiently generate totipotent-like cells for totipotency dissection and for cell lineage trans-differentiation.
Funding Source: This project is supported by Health@InnoHK, Innovation Technology Commission, HKSAR
