Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function

Abstract

Neural stem cells (NSCs) are regarded as a promising therapeutic approach to protecting and restoring damaged neurons in neurodegenerative diseases (NDs) such as Parkinson's disease and Alzheimer's disease (PD and AD, respectively). However, new research suggests that NSC differentiation is required to make this strategy effective. Several studies have demonstrated that melatonin increases mature neuronal markers, which reflects NSC differentiation into neurons. Nevertheless, the possible involvement of mitochondria in the effects of melatonin during NSC differentiation has not yet been fully established. We therefore tested the impact of melatonin on NSC proliferation and differentiation in an attempt to determine whether these actions depend on modulating mitochondrial activity. We measured proliferation and differentiation markers, mitochondrial structural and functional parameters as well as oxidative stress indicators and also evaluated cell transplant engraftment. This enabled us to show that melatonin (25 μM) induces NSC differentiation into oligodendrocytes and neurons. These effects depend on increased mitochondrial mass/DNA/complexes, mitochondrial respiration, and membrane potential as well as ATP synthesis in NSCs. It is also interesting to note that melatonin prevented oxidative stress caused by high levels of mitochondrial activity. Finally, we found that melatonin enriches NSC engraftment in the ND mouse model following transplantation. We concluded that a combined therapy involving transplantation of NSCs pretreated with pharmacological doses of melatonin could efficiently restore neuronal cell populations in PD and AD mouse models depending on mitochondrial activity promotion.

Pan‐cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types

“…Specifically, we found that higher content of melatonin in the tumor microenvironment was associated with less aggressive stage classification and favorable prognosis, which suggested that the melatonergic microenvironment may influence tumor carcinogenesis, prevent the formation of aggressive phenotypes, and therefore result in a decreased risk of death. This is consistent with previous observations that melatonin reduces the susceptibility of gastric mucosal cells to dietary carcinogens through enhanced DNA repair capacity, and inhibits cancer cell proliferation by decreasing DNA synthesis or promoting cell differentiation . Additionally, we demonstrated that the melatonin synthesis/metabolism Index remained an independent prognosticator after including disease stage for adjustment in multivariable models, which implied that melatonin may influence prognosis through other biological mechanisms in addition to tumor carcinogenesis and proliferation.…”

Melatonin promotes proliferation of neural stem cells from adult mouse spinal cord via the PI3K/AKT signaling pathway

“…In this study, we found that the PI3K inhibitor LY294002, but not the ERK1/2 inhibitor U0126, abrogated the stimulatory effect of melatonin on adult spinal cord NSPCs. Melatonin has been shown to modulate the differentiation of NSPCs from adult mouse subventricular zone , while melatonin did not alter the differentiation of NSPCs from adult mouse spinal cord. Together, these results suggest the melatonin has different effects on the differentiation of NSPCs derived from adult mouse brain vs. spinal cord, and regulates the proliferation of NSPCs from the two origins through different signaling pathways.…”

“…Recent studies suggested that melatonin could regulate proliferation and differentiation of adult neural stem cells. Melatonin has been shown to enhance neurosphere formation of cultured neural stem cells from adult mouse subventricular zone, and to promote the differentiation of the stem cells toward neuronal cells [16,17]. Tocharus et al [18] demonstrated that melatonin increased the number of neurospheres from cultured adult rat hippocampal progenitor cells by activating the ERK signaling pathway.…”

“…Recent studies suggested that melatonin could regulate proliferation and differentiation of adult neural stem cells. Melatonin has been shown to enhance neurosphere formation of cultured neural stem cells from adult mouse subventricular zone, and to promote the differentiation of the stem cells toward neuronal cells . Tocharus et al .…”

Melatonin induces mechanisms of brain resilience against neurodegeneration

“…The proposed antiaging and antineurodegenerative properties of melatonin are also driven by mitochondrial function enhancement and the activation of prosurvival pathways . Mitochondrial boost through melatonin may contribute to the neuroprotective and resilience‐promotor effects of this indoleamine. Regarding prosurvival pathways, it is known that melatonin activates the PI3K/Akt signaling pathway .…”