Cell polarization, migration and tissue repair: A promising field for future melatonin research

Melatonin has been shown to support the repair of various tissue injuries. Wound healing is a complicated process that comprises several different cellular activities and regulation mechanisms, such as activation and programming of stem cells, interaction of different cell types, polarization of cells, especially concerning the alternative of pro- vs. anti-inflammatory behavior, migration of cells to the site of replacement, with guidance by other cells and modified extracellular matrix, as observed in the formation of biobridges. In most of these processes, melatonin acts as a decisive modulator, but details depend on tissue and cell types and have not been completely identified. Many aspects will require a considerable amount of work for understanding, in this context, the role of melatonin on a comprehensive basis. Moreover, the modulation of important cell properties has remained partially unknown or has only poorly considered in recent work. For instance, pro- or anti-inflammatory polarization of cells has been described in various cell types, not only in macrophages, in which melatonin is a major regulator, but also in microglia, in astrocytes and in neutrophils. Even in fibroblasts, polarization has been observed and concerns the alternative of inflammatory or fibrotic behavior. Notably, polarized cells that support healing in normal tissue seem to also protect tumors, whereas inflammatory phenotypes show antitumor activities. With regard to antitumor properties of melatonin, it seems necessary to clarify whether melatonin polarizes cells differently in the tumor microenvironment, compared to normal tissue, in which it promotes healing.