title: Vitamin C and l-Proline Antagonistic Effects Capture Alternative States in the Pluripotency Continuum.
abstract: Metabolites and cofactors are emerging as key regulators of cell plasticity and reprogramming, and their role in the control of pluripotency is just being discovered. Here we provide unprecedented evidence that embryonic stem cell (ESC) pluripotency relies on the relative levels of two physiological metabolites, namely ascorbic acid (vitamin C, VitC) and l-proline (l-Pro), which affect global DNA methylation, transcriptional profile, and energy metabolism. Specifically, while a high VitC/l-Pro ratio drives ESCs toward a naive state, the opposite condition (l-Pro excess) captures a fully reversible early primed pluripotent state, which depends on autocrine fibroblast growth factor and transforming growth factor β signaling pathways. Our findings highlight the pivotal role of metabolites availability in controlling the pluripotency continuum from naive to primed states.
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: D'Aniello
authors.affiliation: Department of Molecular Biology, Radboud University, Faculty of Science, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, the Netherlands.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Habibi
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cermola
authors.affiliation: Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli (Napoli), Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Paris
authors.affiliation: Institute for Applied Mathematics "Mauro Picone", CNR, 80131 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Russo
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fiorenzano
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Napoli
authors.affiliation: Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli (Napoli), Italy.
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Melck
authors.affiliation: Department of Biophysics, Biochemistry and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Cobellis
authors.affiliation: Institute for Applied Mathematics "Mauro Picone", CNR, 80131 Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Angelini
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Fico
authors.affiliation: Department of Urology, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Blelloch
authors.affiliation: Institute of Biomolecular Chemistry, CNR, 80078 Pozzuoli (Napoli), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Motta
authors.affiliation: Department of Molecular Biology, Radboud University, Faculty of Science, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy. Electronic address: dario.decesare@igb.cnr.it.
authors.forename: Dario
authors.initials: D
authors.lastname: De Cesare
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy.
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Patriarca
authors.affiliation: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics, 'A. Buzzati-Traverso', CNR, 80131 Naples, Italy. Electronic address: gabriella.minchiotti@igb.cnr.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Minchiotti
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D016000:Cluster Analysis; D019175:DNA Methylation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011392:Proline / Q000494:pharmacology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D011392:Proline; D001205:Ascorbic Acid
keywords: DNA methylation; early primed pluripotency; l-proline; metabolic reprogramming; metabolomics; naive pluripotency; vitamin C