Melatonin‐mediated upregulation of GLUT1 blocks exit from pluripotency by increasing the uptake of oxidized vitamin C in mouse embryonic stem cells

Melatonin and vitamin C are powerful antioxidants that improve the reprogramming efficiency of induced pluripotent stem cells (iPSCs). However, the effects of the combined treatment of vitamin C and melatonin on the differentiation of embryonic stem cells (ESCs) have not yet been examined. In this study, we showed that melatonin synergizes with vitamin C to derail exit from pluripotency of mouse ESCs. This effect is related to the increased uptake of dehydroascorbate, the oxidized form of vitamin C, through glucose transporter 1 (Glut1) transporter, which in turn, is upregulated by melatonin treatment. Analysis of the cell signaling pathway profiling systems and specific pathway inhibition indicated that melatonin enhances Glut1 expression by activating the PI3K/ AKT and MAPK/ERK signaling pathways. Our findings provide a theoretical basis for application of melatonin in research on ESCs and iPSCs and for further investigation of the effect of combinatorial compounds on cell reprogramming. —Wu, H., Song, C., Zhang, J., Zhao, J., Fu, B., Mao, T., Zhang, Y. Melatonin‐mediated upregulation of GLUT1 blocks exit from pluripotency by increasing the uptake of oxidized vitamin C in mouse embryonic stem cells. FASEB J. 31, 1731–1743 (2017) www.fasebj.org