title: Ascorbic acid drives the differentiation of mesoderm-derived embryonic stem cells. Involvement of p38 MAPK/CREB and SVCT2 transporter.
abstract: Here we tested the hypothesis that ascorbic acid (AA) is a signaling molecule acting on stem cells via the differentiation of mesoderm derivatives, including myocytes, osteocytes, and adipocytes.
  
  
  
  Investigations used a murine embryonic stem cell line CGR8 able to differentiate into different cell types and treated or not with ascorbic acid. Differentiation was tracked mainly through cellular anatomy (including presence of beating cardiomyocytes) and expression of specific markers.
  
  
  
  The study demonstrated that AA drives mesoderm-derived stem cell differentiation toward myogenesis and osteogenesis and also inhibits adipogenesis. Further experiments found that AA competes with retinoic acid (RA) to drive cell differentiation in a dose-dependent manner: AA inhibited neurogenic differentiation and stimulated myogenesis whereas RA did the reverse. The AA-dependent differentiation of embryonic stem cells was shown to involve a p38 MAPK/CREB pathway, probably stimulated by cAMP via adenylate cyclases. In addition, SVCT2, the intracellular transporter of AA, acted as a receptor. Finally, we showed that activation/repression of specific differentiation markers is associated with epigenetic changes in their associated promoters. We discuss the impact of these findings in terms of obesity and aging.
authors.affiliation: NORT. UMR INSERM 1062, INRA 1260, Aix-Marseille University, Marseille Cedex 5, France.|Department of Biology, Faculty of Science, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq.
authors.forename: Fryad
authors.initials: F
authors.lastname: Rahman
authors.affiliation: NORT. UMR INSERM 1062, INRA 1260, Aix-Marseille University, Marseille Cedex 5, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Bordignon
authors.affiliation: CNRS-UMR 5088/University of Toulouse-3, Université-Paul-Sabatier, Toulouse Cedex, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Culerrier
authors.affiliation: NORT. UMR INSERM 1062, INRA 1260, Aix-Marseille University, Marseille Cedex 5, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Peiretti
authors.affiliation: TAGC. INSERM U1090, Aix-Marseille University, Marseille Cedex 09, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.affiliation: CNRS-UMR 5088/University of Toulouse-3, Université-Paul-Sabatier, Toulouse Cedex, France.
authors.forename: Malek
authors.initials: M
authors.lastname: Djabali
authors.affiliation: NORT. UMR INSERM 1062, INRA 1260, Aix-Marseille University, Marseille Cedex 5, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Landrier
authors.affiliation: NORT. UMR INSERM 1062, INRA 1260, Aix-Marseille University, Marseille Cedex 5, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Fontes
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects; D024510:Muscle Development / Q000187:drug effects; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D014212:Tretinoin; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid
keywords: Ascorbic acid; Differentiation; Mesoderm derivatives; Obesity; Overweight