Ascorbic acid drives the differentiation of mesoderm-derived embryonic stem cells. Involvement of p38 MAPK/CREB and SVCT2 transporter

Abstract : Scope: 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. Material and methods: 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. Conclusion: 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 activa-tion/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.