Abstract
Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin’s signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation.
Highlights
Academic Editors: Melatonin is a highly pleiotropic signaling molecule that acts on almost all organs and cell types [1]
Extrapineally formed melatonin is poorly released, at least in mammals, whereas the pineal gland plays a privileged role, as it is the major source of circulating melatonin and of the melatonin fraction that enters the third ventricle of the brain via the pineal recess [7,8]
The microvesicles collected from melatonin-pretreated cells were shown to be enriched with USP29 [227], a deubiquitinase that prevents the proteasomal decay of Nrf2, a key transcription factor of anti-inflammatory and antioxidant signaling. This study revealed another novel aspect of mesenchymal stem cells (MSCs) function concerning the stability of Usp29 mRNA, which was enhanced by melatonin, but strongly decreased by overexpression of METTL3
Summary
Academic Editors: Melatonin is a highly pleiotropic signaling molecule that acts on almost all organs and cell types [1]. Numerous studies have demonstrated substantial influences by melatonin on lines of differentiation and fates of stem cells in various tissues, as will be outlined in detail Most of these investigations have dealt with pluripotent cells from adult or adolescent animals or subjects, but a few studies have reported effects on embryonal stem cells. The antioxidant and anti-inflammatory properties of melatonin have been taken as a reason for protecting stem cells against oxidative and inflammatory insults [13,15,19,20,21,22,23,24,25,26,27] This information is of high value, it largely exceeds the topic of stem cell programming. These concern the initial involvement of the G protein-coupled membrane receptors, MT1 and MT2 , and their primary transmission processes such as decreases of cAMP or activation of MAP kinase pathways [28], and various downstream processes referred to as the extended signaling by melatonin, which may comprise activation of sirtuin-1 (SIRT1), or regulation of noncoding RNAs, such as miRNAs, lncRNAs, or circRNAs [29,30]
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