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

Daniel Ortmann; Stephanie Brown; Anne 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 A Churchill; Christopher L Baker; Peter J Rugg-Gunn; Steven C Munger; Laura G Reinholdt; Ludovic Vallier

doi:10.1016/j.stem.2020.07.019

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.

Authors

Daniel Ortmann¹, Stephanie Brown², Anne Czechanski³, Selcan Aydin³, Daniele Muraro⁴, Yuanhua Huang⁵, Rute A Tomaz², Anna Osnato², Giovanni Canu², Brandon T Wesley², Daniel A Skelly³, Oliver Stegle⁶, Ted Choi³, Gary A Churchill³, Christopher L Baker³, Peter J Rugg-Gunn⁷, Steven C Munger³, Laura G Reinholdt³, Ludovic Vallier⁸

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: daniel.ortmann@gmail.com.
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: lv225@cam.ac.uk.

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

Abstract

Publication types

MeSH terms

Grants and funding