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

Mendivil-Perez, Miguel et al.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.This study was partially funded by the following grants: SAF2009-14037 from the Spanish Ministry of Economy and Competitivity (MINECO), CB/10/00238 from the Carlos III Health Institute, GREIB.PT_2010_04 from the CEIBiotic Program of the University of Granada, Spain, and CTS-101 from the Innovation, Science and Business Council, Junta de Andalucía, Spain. The study was carried out within the framework of the “Convenio Marco 206-2012” agreement between the University of Antioquia in Colombia and the University of Granada in Spain. MJ-Del-Rio and CV-P were supported by Colciencias grants #1115-657-740786 (contract 623-2014). MM-P and V-SM are associate researchers. MM-P is funded by the Colciencias, Enlaza-Mundos, and AUIP mobility programs. VS-M was funded by the AUIP mobility program.Peer Reviewe