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L-Proline Induces a Mesenchymal-like Invasive Program in Embryonic Stem Cells by Remodeling H3K9 and H3K36 Methylation

2013; Elsevier BV; Volume: 1; Issue: 4 Linguagem: Inglês

10.1016/j.stemcr.2013.09.001

2213-6711

Stefania Comes, Miriam Gagliardi, Nicola Laprano, Annalisa Fico, Amelia Cimmino, Andrea Palamidessi, Dario De Cesare, Sandro De Falco, Claudia Angelini, Giorgio Scita, Eduardo J. Patriarca, Maria R. Matarazzo, Gabriella Minchiotti,

Tissue Engineering and Regenerative Medicine

Metabolites are emerging as key mediators of crosstalk between metabolic flux, cellular signaling, and epigenetic regulation of cell fate. We found that the nonessential amino acid L-proline (L-Pro) acts as a signaling molecule that promotes the conversion of embryonic stem cells into mesenchymal-like, spindle-shaped, highly motile, invasive pluripotent stem cells. This embryonic-stem-cell-to-mesenchymal-like transition (esMT) is accompanied by a genome-wide remodeling of the H3K9 and H3K36 methylation status. Consistently, L-Pro-induced esMT is fully reversible either after L-Pro withdrawal or by addition of ascorbic acid (vitamin C), which in turn reduces H3K9 and H3K36 methylation, promoting a mesenchymal-like-to-embryonic-stem-cell transition (MesT). These findings suggest that L-Pro, which is produced by proteolytic remodeling of the extracellular matrix, may act as a microenvironmental cue to control stem cell behavior.