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.

中文翻译：

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褪黑素通过BiP / NRF1途径激活ABCA1，以抑制高胆固醇诱导的间充质干细胞凋亡

肥胖症患者的伤口愈合迟缓会增加与血管供血不足和氧化应激相关的并发症的风险。肥胖患者的高胆固醇水平与移植的脐血来源的间充质干细胞（UCB-MSCs）的凋亡有关。褪黑素通过人们尚不清楚的机制有助于预防肥胖症患者的胆固醇积聚。因此，我们研究了褪黑激素在胆固醇诱导的细胞凋亡中的调控机制。在UCB-MSCs中研究了褪黑激素对胆固醇诱导的细胞凋亡的保护作用。我们使用诱发肥胖的小鼠模型显示褪黑素治疗可恢复移植的UCB-MSC的存活率及其伤口愈合能力。使用Student's t检验比较治疗组和对照组的平均值，并使用Dunnett多重比较检验通过单向方差分析分析三组或更多组之间的差异。褪黑素治疗增加了ATP结合盒A成员1成员（ABCA1）的表达，从而减少了胆固醇的积累和胆固醇诱导的细胞凋亡。小鼠皮肤伤口愈合模型表明，褪黑素治疗可恢复移植的UCB-MSC的存活率和肥胖小鼠的伤口愈合能力。褪黑素通过调节MT2 / Sp1依赖性microRNA-597-5p抑制结合免疫球蛋白（BiP）的表达。褪黑素降低了BiP与核因子红系2相关因子1（NRF1）的共定位，导致ABCA1表达增加。褪黑素通过ABCA1诱导细胞内胆固醇的流出，从而通过依赖MT2的BiP / NRF1途径减少UCB-MSC的凋亡。