Figure 7. Pluripotent states are “metastable”.

Model summarizing the requirements for in vitro stabilization of different pluripotent states in 129 (left half) and NOD mouse strains (right half). “Metastability” pertains to describing a system with two or more equilibrium states (indicated by the stippled grey horizontal lines) that can interconvert by defined signals. The ICM-like state is characterized by a greater developmental potential than the EpiSCs-like state. The factors required for stabilizing the respective pluripotent states in the different genetic backgrounds are indicated in green on the plateau lines for each state. The ICM-like pluripotent state in permissive 129 cells, whether achieved by direct in vitro reprogramming or by ICM explantation is stabilized by Lif/Stat3 signaling, while the bFGF/Activin/Nodal signaling stabilizes the EpiSC-like state. Defined transcription factor or small molecules convert the EpiSC-like cells to the ICM-like ES cell state (highlighted in orange on the left). The 129 and NOD EpiSC-states are indistinguishable in their stability and growth condition requirements and can be reverted into ICM-like pluripotency by expression of Klf4 or c-Myc or by specific inhibitors added to the medium. However, the ICM-ES like state is unstable on the NOD genetic background and requires continuous expression of exogenous factors in addition to Lif (dashed black and red arrows).