Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency

Alessandro Fiorenzano, Emilia Pascale, Cristina D'Aniello, Dario Acampora, Cecilia Bassalert, Francesco Russo, Gennaro Andolfi, Mauro Biffoni, Federica Francescangeli, Ann Zeuner, Claudia Angelini, Claire Chazaud, Eduardo J. Patriarca, Annalisa Fico () and Gabriella Minchiotti ()
Additional contact information
Alessandro Fiorenzano: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR
Emilia Pascale: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR
Cristina D'Aniello: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR
Dario Acampora: Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR
Cecilia Bassalert: Inserm, UMR1103, F-63001; CNRS, UMR6293, F-63001; Université Clermont Auvergne, Laboratoire GReD, BP 10448
Francesco Russo: Institute for Applied Mathematics ‘Mauro Picone’, CNR
Gennaro Andolfi: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR
Mauro Biffoni: Oncology and Molecular Medicine, Istituto Superiore di Sanità
Federica Francescangeli: Oncology and Molecular Medicine, Istituto Superiore di Sanità
Ann Zeuner: Oncology and Molecular Medicine, Istituto Superiore di Sanità
Claudia Angelini: Institute for Applied Mathematics ‘Mauro Picone’, CNR
Claire Chazaud: Inserm, UMR1103, F-63001; CNRS, UMR6293, F-63001; Université Clermont Auvergne, Laboratoire GReD, BP 10448
Eduardo J. Patriarca: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR
Annalisa Fico: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR
Gabriella Minchiotti: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics ‘A. Buzzati-Traverso’, CNR

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract Known molecular determinants of developmental plasticity are mainly transcription factors, while the extrinsic regulation of this process has been largely unexplored. Here we identify Cripto as one of the earliest epiblast markers and a key extracellular determinant of the naive and primed pluripotent states. We demonstrate that Cripto sustains mouse embryonic stem cell (ESC) self-renewal by modulating Wnt/β-catenin, whereas it maintains mouse epiblast stem cell (EpiSC) and human ESC pluripotency through Nodal/Smad2. Moreover, we provide unprecedented evidence that Cripto controls the metabolic reprogramming in ESCs to EpiSC transition. Remarkably, Cripto deficiency attenuates ESC lineage restriction in vitro and in vivo, and permits ESC transdifferentiation into trophectoderm lineage, suggesting that Cripto has earlier functions than previously recognized. All together, our studies provide novel insights into the current model of mammalian pluripotency and contribute to the understanding of the extrinsic regulation of the first cell lineage decision in the embryo.

Date: 2016
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DOI: 10.1038/ncomms12589

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