Melatonin-Induced PGC-1α Improves Angiogenic Potential of Mesenchymal Stem Cells in Hindlimb Ischemia
Jun Hee Lee1,2, Yong-Seok Han1 and Sang Hun Lee1,2,*
1Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401,
2Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31538, Republic of Korea
E-mail: ykckss1114@nate.com
Tel: +82-2-709-9029, Fax: +82-2-792-5812
Received: August 12, 2019; Revised: October 1, 2019; Accepted: October 22, 2019; Published online: November 18, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
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 proliferator-activated 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.
Keywords: Melatonin, Mesenchymal stem cells, PGC-1α, Hindlimb ischemia, Cell-based therapy


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