Interlinked Bi-stable Switches Govern the Cell Fate Commitment of Embryonic Stem Cells

Cell fate decision-making events of embryonic stem (ES) cells are often governed by bi-stable switch-like steady state dynamics of two key transcription factors Oct4 and Nanog due to mutual positive feedback regulation. Intriguingly, for the differentiation of ES cells to either extraembryonic trophectoderm (TE) and primitive endoderm (PrE) lineages, Oct4 maintains either low (TE) or high PrE) expression levels relative to a moderate level in ES cells, while Nanog exhibits high expression in ES state and low expression in both the differentiated states. The dynamical origin for such kind of disparate steady-state level maintenance of Oct4 and Nanog remains elusive. Herein, we demonstrate that such complex steady-state dynamics can be hypothesized and explained by two different bistable switches interconnected either in a stepwise (Oct4) or in a mushroom-like (Nanog) manner. Our hypothesis qualitatively reconciles various experimental observations and elucidates how different feedback and feed-forward 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.