Abstract: Melatonin is a hormone, synthesized in the pineal gland, which primarily controls the circadian rhythm of the body. In recent years, melatonin has also been shown to regulate metabolism, provide neuroprotection, and act as an anti-inflammatory, free radical scavenger. There has also been a recent research interest in the role of melatonin in regulating mesenchymal stromal cells (MSCs). MSCs are pivotal for their ability to differentiate into a variety of different tissues. There is also increasing evidence for the therapeutic prospects of MSCs via paracrine signaling. In addition to secreting cytokines and chemokines, MSCs can secrete extracellular vesicles (EVs), allowing them to respond to injury and promote tissue regeneration. While there has been a major research interest in the use of MSCs for regenerative medicine, the clinical application is limited by many risks, including tumorigenicity, senescence, and sensitivity to toxic environments. The use of MSC-derived EVs for cell-free therapy can potentially avoid the disadvantages of MSCs, which makes this an exciting prospect for regenerative medicine. Prior research has shown that MSCs, via paracrine mechanisms, can identify receptor-independent responses to melatonin and then activate a series of downstream pathways, which exert a variety of effects, including anti-tumor and anti-inflammatory effects. Here we review the synthesis of melatonin, its mechanisms of action, and the effect of melatonin on MSCs via paracrine signaling. Furthermore, we summarize the current clinical applications of melatonin and discuss future prospects.
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