BCL2 Facilitates Naïve Pluripotency and an 8C ‐Like State in Human Embryonic Stem Cells

Human naïve embryonic stem cells (ESCs) can spontaneously transition into 8‐cell‐like cells (8CLCs), a cell state that recapitulates the totipotent features of the 8‐cell‐stage embryo. However, the regulatory circuitry underlying this reprogramming process remains poorly elucidated. Here, we show that BCL2 contributes to 8CLC induction. We demonstrate that BCL2 not only stabilizes the human naïve pluripotent state via H3K27ac associated epigenetic modulation but also induces and sustains 8CLC self‐renewal under chemically defined culture conditions. Mechanistically, BCL2 safeguards the expression of core pluripotency genes, endowing cells with self‐renewal capacity and lineage‐biased differentiation capacity, enabling their contribution to both embryonic and extra‐embryonic lineages in chimeric embryos. Notably, BCL2 primes human ESCs to gain competitive dominance in the mouse ESC niche, suppresses mesodermal lineage commitment, and enhances trophoblast differentiation. Taken together, our findings reveal a role for BCL2 in regulating pluripotency and promoting the acquisition of an 8C‐like state, providing a useful in vitro system for exploring the regulatory mechanisms of stem cell plasticity.