Asymmetric Division in a Two-Cell-Like State Rejuvenates Embryonic Stem Cell Lineage

An intriguing question in biology is whether all cells age. Embryonic stem cells (ESCs) stand out as a rare normal cell type capable of indefinite in vitro passage. However, it remains unclear how ESC lineage immortality is achieved and whether individual ESCs are immortal. In this study, we show that lineage renewal of ESCs can be attributed to a distinctive state that they sporadically enter, characterized by the expression of molecular markers resembling those found in two-cell (2C) embryos. During this 2C-like state, cells undergo asymmetric divisions, giving rise to one branch that dies, and the other that reverts to the pluripotent state. Importantly, the lineage emerging from the latter branch exhibits signs of rejuvenation, including reduced DNA damage and an enhanced chimeric efficiency. Taken together, these findings underscore the crucial role of asymmetric cell division in maintaining long-term health of the ESC lineage against mounting damage within individual cells.