Efficient Reprogramming of Mouse Embryonic Stem Cells into Trophoblast Stem-like Cells via Lats Kinase Inhibition

Simple Summary In this study, we investigated the critical process of cell fate determination in mouse embryos, focusing on the transition from embryonic stem cells (ESC) to trophoblast stem-like cells (TSLC). As ESCs and TSCs have distinct lineage differences and functional boundaries, the natural conversion between them is hindered. Through the inhibition of LATS kinase, we not only facilitated the conversion of inner cell mass (ICM) to trophectoderm (TE), but also successfully transformed ESC into stable self-renewing TSLC. Our findings highlighted the distinct molecular properties of TSLC, including the high expression of marker genes, such as Cdx2 and Eomes, closely resembling those of trophoblast stem cells (TSC). Furthermore, TSLC demonstrated the ability to differentiate into mature trophoblast cells in vitro and actively participated in placenta formation in vivo.Abstract Mouse zygotes undergo multiple rounds of cell division, resulting in the formation of preimplantation blastocysts comprising three lineages: trophectoderm (TE), epiblast (EPI), and primitive endoderm (PrE). Cell fate determination plays a crucial role in establishing a healthy pregnancy. The initial separation of lineages gives rise to TE and inner cell mass (ICM), from which trophoblast stem cells (TSC) and embryonic stem cells (ESC) can be derived in vitro. Studying lineage differentiation is greatly facilitated by the clear functional distinction between TSC and ESC. However, transitioning between these two types of cells naturally poses challenges. In this study, we demonstrate that inhibiting LATS kinase promotes the conversion of ICM to TE and also effectively reprograms ESC into stable, self-renewing TS-like cells (TSLC). Compared to TSC, TSLC exhibits similar molecular properties, including the high expression of marker genes such as Cdx2, Eomes, and Tfap2c, as well as hypomethylation of their promoters. Importantly, TSLC not only displays the ability to differentiate into mature trophoblast cells in vitro but also participates in placenta formation in vivo. These findings highlight the efficient reprogramming of ESCs into TSLCs using a small molecular inducer, which provides a new reference for understanding the regulatory network between ESCs and TSCs.