Interlinked bi‐stable switches govern the cell fate commitment of embryonic stem cells

The development of embryonic stem (ES) cells to extraembryonic trophectoderm and primitive endoderm lineages manifests distinct steady‐state expression patterns of two key transcription factors—Oct4 and Nanog. How dynamically such kind of steady‐state expressions are maintained remains elusive. Herein, we demonstrate that steady‐state dynamics involving two bistable switches which are interlinked via a stepwise (Oct4) and a mushroom‐like (Nanog) manner orchestrate the fate specification of ES cells. Our hypothesis qualitatively reconciles various experimental observations and elucidates how different feedback and feedforward motifs orchestrate the extraembryonic development and stemness maintenance of ES cells. Importantly, the model predicts strategies to optimize the dynamics of self‐renewal and differentiation of embryonic stem cells that may have therapeutic relevance in the future.