Naive Pluripotent Stem Cells Exhibit Phenotypic Variability that Is Driven by Genetic Variation.

Daniel Ortmann
Stephanie Brown
Anne M Czechanski
Selcan Aydin
Daniele Muraro
Yuanhua Huang
Rute A Tomaz
Anna Osnato
Giovanni Canu
Brandon T Wesley
Daniel A Skelly
Oliver Stegle
Ted Choi
Gary Churchill
Christopher L. Baker
Peter J Rugg-Gunn
Steven C. Munger
Laura G Reinholdt
Ludovic Vallier


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.