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Melatonin (MEL) may influence the efficiency of reprogramming both by somatic cell nuclear transfer and by direct induction of pluripotent stem cells (iPSC) through a yet unidentified mechanism. Transcription factors linked to cell reprogramming and cell signalling may be differentially expressed according to cell differentiation status. To address the effect of MEL on the expression of transcription factors linked to reprogramming, we used two distinct in vitro models of cellular plasticity: human foreskin fibroblasts (HFF) and primary human granulosa-lutein cells (GLC). Real-time quantitative polymerase chain reaction (qRT-PCR) analysis revealed amplification of transcripts for KLF4, MYC and NANOG in both cell types. In GLC, treatment with 10 nmol/L of MEL provoked significant up-regulation of the expression of MYC and NANOG compared to controls. KLF4 expression was not altered in GLC but was significantly down-regulated in MEL-treated HFF cells. Alterations in the expression of ERK1/2 and pERK1/2 in GLC as analyzed by Western blot were not observed regardless of the MEL treatment. On the contrary, HFF cells responded to MEL treatment with 1.6-fold higher levels of pERK1/2 compared to the non-treated controls. Our data suggest that the activation of MT1 melatonin receptor is probably related to phosphorylation of ERK1/2 at least in expanding HFF, which subsequently may act to alter gene expression and regulate cell fate. In conclusion, we demonstrated for the first time, the selective effect of MEL in vitro at physiological concentration on transcription factors regulating pluripotency and differentiation in human non-cancer cells according to cell differentiation status. [ABSTRACT FROM AUTHOR]