1. Dual inhibition (2i) supports the pluripotency core network (OSN), while LIF stabilizes PSCs
Dual inhibition (2i) supports the pluripotency core network (OSN), while LIF stabilizes PSCs Representative bright‐field microscope images of mESC colonies in LIF and 2iL conditions with serum. The 2i condition consists of CHIR99021(CH) and PD (PD).Schematic illustration of the PSC metrics. The frequency of OSN‐high cells reflects the population‐level pluripotentiality. Sustainability reflects the intrinsic network stability during maintenance of the PSC state in the absence of extrinsic stimuli. Susceptibility measures the change of expression profiles to perturbations such as gene manipulations and signaling inputs and predicts the chance of PSC fate change. The link width among OSN in each condition represents the Pearson's correlations among OSN.(i) Pluripotency level (OSN expression) of each PSC‐associated SCC. (ii) Sustainability scores for each PSC‐associated SCC. (iii) Susceptibility of gene expression profiles against minimal perturbation to GRN topology was assessed in silico by measuring the change of variance in all genes. The error bars represent s.d. of five independent simulations.Predicted population‐averaged gene expression levels of OSN in SCCs from all possible combinations of signal inputs (white—without LIF, orange—with LIF, red—with 2iL, and blue—with 2i−L).Four signaling pathways are manipulated in 16 conditions that are divided into four groups based on LIF and Wnt signal manipulations: +L+W (red, 2iL), −L+W (blue, 2iJ), +L−W (orange), and −L−W (white). Note that 2i+JAKi (2iJ) is the in vitro counterpart to the in silico 2i−L.High content screening results of gene‐expressing cell frequency (x‐axis) and predicted population‐averaged expression levels (y‐axis) of OSN. Each condition is tested under activated and repressed Activin A/Nodal and BMP signals by addition of cytokines or inhibitors (±A±B). The symbol + indicates the addition of cytokines or small molecules that results in activation of the signaling pathway, and the symbol − indicates the addition of inhibitors to pathway activity. Circles are 16 combinatorial signal conditions, and triangles are the three control PSC conditions and are colorized using the same scheme outlined in (E). Experimental data are represented as mean and s.d. of three experiments, each performed in two replicates, and simulation data represent five independent simulations. Source data are available online for this figure.
Ayako Yachie‐Kinoshita et al. Mol Syst Biol 2018;14:e7952
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