Biological effects of melatonin on human adipose-derived mesenchymal stem cells

Background Mesenchymal stem cells (MSCs) capable of differentiating into other cell types and having immunomodulatory effects are affected by a variety of intrinsic and/or extrinsic signaling factors, including growth factors, cytokines, extracellular matrix, and hormones. Melatonin made by the pineal gland is a hormone that regulates sleep cycles. Recent studies show that melatonin improves the therapeutic effects of stem cells. Here, we aimed to investigate whether melatonin enhances biological activities of human adipose-derived MSCs (AdMSCs). Methods AdMSCs were obtained from normal healthy donors after obtaining written informed consent. Cell proliferation assay was performed by using EZ-cytox based on WST. To evaluate the stemness of AdMSCs, CFU and β-galactosidase assay were performed. To investigate the effects of melatonin on suppression of T cells proliferation, human peripheral blood mononuclear cells were co-cultured with AdMSC. 10 μM of melatonin and 5 μM of luzindole were treated, and 10 μg/ml phytohaemagglutinin was applied for activation of T cells. Results Melatonin promoted cell proliferation by inducing Sox2 gene and preventing replicative senescence. In addition, melatonin has anti-adipogenesis effects on MSCs. In PCR analysis, C/EPB gene, a key transcription factor of adipogenesis, was decreased by melatonin, resulting in reduced adipogenic differentiation in vitro assay. We also examined immunomodulatory effects using co-culture system of human peripheral blood mononuclear cells and MSCs. Activated T cells exposed to melatonin were strongly inhibited compared to the control. We have confirmed the favourable effects of melatonin on MSCs by using luzindole, a selective melatonin receptor antagonist. Conclusion The proliferation-accelerating, anti-inflammatory effects of melatonin suggest that melatonin-mediated MSCs will be used for effective cellular therapy (This work was supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (No. NRF-2018R1D1A1B07050071)).