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Vitamin C and l-Proline Antagonistic Effects

February 14, 2017

In this article, Minchiotti, De Cesare, and colleagues show that the relative levels of two physiological metabolites, vitamin C and l-proline, direct ESCs toward naive or reversible primed states of pluripotency, placed between the naive/2i and FGF/activin states, and highlight a pivotal role of metabolic-epigenetic crosstalk in the developmental continuum.

Vitamin C and l-Proline Antagonistic Effects Capture Alternative States in the Pluripotency Continuum

Cristina D’Aniello, Ehsan Habibi, Federica Cermola, Debora Paris, Francesco Russo, Alessandro Fiorenzano, Gabriele Di Napoli, Dominique J. Melck, Gilda Cobellis, Claudia Angelini, Annalisa Fico, Robert Blelloch, Andrea Motta, Hendrik G. Stunnenberg, Dario De Cesare, Eduardo J. Patriarca, and Gabriella Minchiotti.


  • Epigenetic modifiers facilitate induction and quality of porcine iPSCs
  • Tet1, Tet3, or Kdm3a increases naive pluripotency network in association with Rex1
  • Unlike cytoplasmic Rex1, nuclear expression of Rex1 is associated with high pluripotency
  • HDAC inhibitors further activate Rex1 and reduce reliance on the exogenous genes


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.


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