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

Cell Stem Cell. 2020 Sep 3;27(3):470-481.e6. doi: 10.1016/j.stem.2020.07.019. Epub 2020 Aug 13.

Abstract

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.

Keywords: differentiation; eQTL; genetics; ground state; mouse embryonic stem cells; naïve; pluripotent stem cells; signaling; variability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Variation, Population
  • Cell Differentiation / genetics
  • Genetic Variation
  • Induced Pluripotent Stem Cells*
  • Mice
  • Pluripotent Stem Cells*
  • Reproducibility of Results