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.