Despite the
therapeutic effect of mesenchymal stem cells (MSCs) in ischemic diseases, pathophysiological conditions, including
hypoxia, limited nutrient availability, and oxidative stress restrict their potential. To address this issue, we investigated the effect of
melatonin on the bioactivities of MSCs. Treatment of MSCs with
melatonin increased the expression of peroxisome proliferatoractivated receptor gamma coactivator-1 alpha (PGC-1α).
Melatonin treatment enhanced mitochondrial oxidative phosphorylation in MSCs in a PGC-1α-dependent manner.
Melatonin-mediated PGC-1α expression enhanced the proliferative potential of MSCs through regulation of cell cycle-associated
protein activity. In addition,
melatonin promoted the angiogenic ability of MSCs, including migration and invasion abilities and secretion of angiogenic
cytokines by increasing PGC-1α expression. In a murine hindlimb
ischemia model, the survival of transplanted
melatonin-treated MSCs was significantly increased in the ischemic tissues, resulting in improvement of functional recovery, such as blood perfusion,
limb salvage, neovascularization, and protection against
necrosis and
fibrosis. These findings indicate that the
therapeutic effect of
melatonin-treated MSCs in ischemic diseases is mediated via regulation of PGC-1α level. This study suggests that
melatonin-induced PGC-1α might serve as a novel target for MSC-based
therapy of ischemic diseases, and
melatonin-treated MSCs could be used as an effective cell-based therapeutic option for patients with ischemic diseases.