Distinct Signaling Requirements for the Establishment of ESC Pluripotency in Late-Stage EpiSCs
Damir Jacob Illich,
Miao Zhang,
Andrei Ursu,
Rodrigo Osorno,
Kee-Pyo Kim,
Juyong Yoon,
Marcos J. Araúzo-Bravo,
Guangming Wu,
Daniel Esch,
Davood Sabour,
Douglas Colby,
Kathrin S. Grassme,
Jiayu Chen,
Boris Greber,
Susanne Höing,
Wiebke Herzog,
Slava Ziegler,
Ian Chambers,
Shaorong Gao,
Herbert Waldmann,
Hans R. Schöler
Affiliations
Damir Jacob Illich
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Miao Zhang
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Andrei Ursu
Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Rodrigo Osorno
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Kee-Pyo Kim
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Juyong Yoon
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Marcos J. Araúzo-Bravo
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Guangming Wu
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Daniel Esch
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Davood Sabour
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Douglas Colby
MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, Scotland
Kathrin S. Grassme
University of Münster, 48149 Münster, Germany
Jiayu Chen
School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
Boris Greber
Human Stem Cell Pluripotency Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany
Susanne Höing
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Wiebke Herzog
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
Slava Ziegler
Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Ian Chambers
MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, Scotland
Shaorong Gao
School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
Herbert Waldmann
Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Hans R. Schöler
Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany
It has previously been reported that mouse epiblast stem cell (EpiSC) lines comprise heterogeneous cell populations that are functionally equivalent to cells of either early- or late-stage postimplantation development. So far, the establishment of the embryonic stem cell (ESC) pluripotency gene regulatory network through the widely known chemical inhibition of MEK and GSK3beta has been impractical in late-stage EpiSCs. Here, we show that chemical inhibition of casein kinase 1alpha (CK1alpha) induces the conversion of recalcitrant late-stage EpiSCs into ESC pluripotency. CK1alpha inhibition directly results in the simultaneous activation of the WNT signaling pathway, together with inhibition of the TGFbeta/SMAD2 signaling pathway, mediating the rewiring of the gene regulatory network in favor of an ESC-like state. Our findings uncover a molecular mechanism that links CK1alpha to ESC pluripotency through the direct modulation of WNT and TGFbeta signaling.
