Hmgn3 is critical for inducing totipotency in mouse embryonic stem cells

Mouse embryonic stem cells (ESCs) have emerged as ideal tools for developmental biology research due to their characteristics such as unlimited proliferation and pluripotent differentiation potential. However, these stem cells are unable to differentiate into extraembryonic tissues like the placenta and yolk sac. Therefore, there is an urgent need to develop totipotent stem cells with higher differentiation potential to adapt to the rapidly advancing field of developmental biology.

Totipotency refers to the highest developmental potential of a cell, enabling it to differentiate into all cell types of a fetus as well as its extraembryonic appendages (including the placenta, yolk sac, etc.). In recent years, researchers have been able to obtain totipotent-like stem cells to a certain extent by optimizing culture medium, yet the precise regulatory mechanism underlying this process remains unclear.

In this study, Wang et al., successfully established an Hmgn3-overexpressing embryonic stem cell line (Hmgn3-OE ESCs), which exhibits advanced cellular plasticity compared to wild-type ESCs. Through chimeric experiments, it is found that overexpression of Hmgn3 enables these cells to stably contribute to the fetus, placenta, and yolk sac in vivo. Additionally, Hmgn3-OE ESCs can efficiently self-organize into blastoid-like structures (Blastoids) in vitro, displaying cellular molecular and developmental properties highly similar to those of wild-type blastocysts. This further confirms their totipotency. In contrast, knockout of Dux—a key downstream gene of Hmgn3—significantly impairs totipotency of Hmgn3-OE ESCs. These results demonstrate the great potential of the single gene Hmgn3 in activating totipotency in mESCs and constructing artificial embryo models. This study provides a novel and efficient platform for research on the expansion of stem cell differentiation and the regulation of early embryonic development.

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