Melatonin activates ABCA1 via the BiP/NRF1 pathway to suppress high-cholesterol-induced apoptosis of mesenchymal stem cells

Abstract

Background 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. Methods 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. Results 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. Conclusion Melatonin induced the efflux of intracellular cholesterol through ABCA1 to decrease apoptosis of UCB-MSCs via an MT2-dependent BiP/NRF1 pathway.

Andrographolide protects bone marrow mesenchymal stem cells against glucose and serum deprivation under hypoxia via the NRF2 signaling pathway

“…Cell precipitates were stained with 0.1% trypan blue (Beyotime, Shanghai, China) as described. The live cell rate (%) was calculated as the number of living cells (trypan blue-negative cells)/the total cell number [ 36 ].…”

Melatonin and the Programming of Stem Cells

“…Improved wound healing in the skin was achieved by transplanting umbilical cord MSCs with support by melatonin treatment [18]. Hepatic tissue repair for the purpose of ameliorating liver fibrosis was performed with melatonin-preconditioned BMSCs [14] or dental pulp MSCs [12].…”

“…The present article will not discuss in detail all the different aspects of melatonin effects in connection with stem cells. For instance, a number of studies has dealt with adjunctive roles of melatonin for the success of transplantation or injection of stem cells at injured or dysfunctional sites [10][11][12][13][14][15][16][17][18]. Similarly, the antioxidant and anti-inflammatory properties of melatonin have been taken as a reason for protecting stem cells against oxidative and inflammatory insults [13,15,[19][20][21][22][23][24][25][26][27].…”

Melatonin induces fat browning by transdifferentiation of white adipocytes andde novodifferentiation of mesenchymal stem cells

“…In addition, other effects of melatonin were recently demonstrated on mesenchymal stem cells derived from the umbilical cord blood of obese rodents that reduce cholesterol accumulation and prevent apoptosis of MSCs, supporting the therapeutic role of melatonin against obesity. 78 A recent meta-analysis of the effects of melatonin in human obesity studies showed that, despite the evidence found in the energy balance of rodents and humans, 79,80 the real impact of melatonin on body weight loss remains unclear due to the inconsistent melatonin treatment schedule regarding duration and low dose (0.01-0.1 mg kg −1 day −1 ) in all studies. Overall, these data provide evidence that, under melatonin treatment, the de novo differentiation of beige cells in ZDF rats and humans probably occurs in conjunction.…”