Summary Variability among pluripotent stem cell (PSC) lines is a prevailing issue that hampers not only experimental reproducibility but also large-scale applications and personalized cell-based therapy. This variability could result from epigenetic and genetic factors that influence stem cell behavior. Naive culture conditions minimize epigenetic fluctuation, potentially overcoming differences in PSC line differentiation potential. Here we derived PSCs from distinct mouse strains under naive conditions and show that lines from distinct genetic backgrounds have divergent differentiation capacity, confirming a major role for genetics in PSC phenotypic variability. This is explained in part through inconsistent activity of extra-cellular signaling, including the Wnt pathway, which is modulated by specific genetic variants. Overall, this study shows that genetic background plays a dominant role in driving phenotypic variability of PSCs.
Graphical Abstract
Highlights • Ground-state mESCs are variable in gene expression and capacity of differentiation • Genetic background contributes to ESC variability even after epigenetic resetting • Signaling pathway activity is influenced by genetic traits • Analysis of eQTL identifies genetic elements causing variability
Ortmann et al. show that ground-state pluripotent stem cells exhibit variability in gene expression and differentiation propensity that is associated with their genetic background. This variability is linked to differences in major signaling pathway activity, showing that analyses of expression quantitative trait loci enable identification of causal genetic elements.