Title |
Melatonin activates ABCA1 via the BiP/NRF1 pathway to suppress high-cholesterol-induced apoptosis of mesenchymal stem cells
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Published in |
Stem Cell Research & Therapy, February 2021
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DOI | 10.1186/s13287-021-02181-4 |
Pubmed ID | |
Authors |
Jun Sung Kim, Young Hyun Jung, Hyun Jik Lee, Chang Woo Chae, Gee Euhn Choi, Jae Ryong Lim, Seo Yihl Kim, Joo Eun Lee, Ho Jae Han |
Abstract |
Retarded wound healing in patients with obesity contributes to a risk of complications associated with vascular insufficiency and oxidative stress. The high cholesterol levels of patients with obesity are associated with apoptosis of engrafted umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). Melatonin contributes to the prevention of cholesterol accumulation in patients with obesity via a mechanism that is poorly understood. We therefore investigated the regulatory mechanism of melatonin in cholesterol-induced apoptosis. The protective effects of melatonin on cholesterol-induced apoptosis were investigated in UCB-MSCs. We used a mouse model of induced obesity to show that melatonin treatment restored the survival rate of transplanted UCB-MSCs and their wound-healing capacity. The mean values of the treatment groups were compared with those of the control group using Student's t test, and differences among three or more groups were analyzed using one-way analysis of variance with Dunnett's multiple comparison test. Melatonin treatment increased the expression of ATP-binding cassette subfamily A member 1 (ABCA1), which reduced cholesterol accumulation and cholesterol-induced apoptosis. The mouse skin wound healing model showed that melatonin treatment restored the survival rate of transplanted UCB-MSCs and the wound-healing capacity of obese mice. Melatonin inhibited the expression of binding immunoglobulin protein (BiP) through the regulation of MT2/Sp1-dependent microRNA-597-5p. Melatonin decreased the co-localization of BiP with nuclear factor erythroid 2-related factor 1 (NRF1), which resulted in increased ABCA1 expression. Melatonin induced the efflux of intracellular cholesterol through ABCA1 to decrease apoptosis of UCB-MSCs via an MT2-dependent BiP/NRF1 pathway. |
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