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

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.
Daniel Ortmann 1,  Stephanie Brown 2,  Anne Czechanski 3,  Selcan Aydin 3,  Daniele Muraro 4,  Yuanhua Huang 5,  Rute A Tomaz 2,  Anna Osnato 2,  Giovanni Canu 2,  Brandon T Wesley 2,  Daniel A Skelly 3,  Oliver Stegle 6,  Ted Choi 3,  Gary A Churchill 3,  Christopher L Baker 3,  Peter J Rugg-Gunn 7,  Steven C Munger 3,  Laura G Reinholdt 3,  Ludovic Vallier 8
Affiliations

Affiliations

  • 1 Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge, Cambridge, UK. Electronic address: [email protected].
  • 2 Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge, Cambridge, UK.
  • 3 Jackson Laboratory, Bar Harbor, ME, USA.
  • 4 Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • 5 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK.
  • 6 European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK; European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany; Division of Computational Genomics and Systems Genetics, German Cancer Research, Center (DKFZ), Heidelberg, Germany.
  • 7 Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Epigenetics Programme, Babraham Institute, Cambridge, UK.
  • 8 Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge, Cambridge, UK. Electronic address: [email protected].
PMID: 32795399 DOI: 10.1016/j.stem.2020.07.019
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.

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