Fang Jia, Yan Yuan, Teng Xin, Wen Xinyu, Li Na, Peng Sha, Liu Wenshuai, Donadeu F Xavier, Zhao Shanting, Hua Jinlian
College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and Technology, Northwest A and F University, Yangling, Shaanxi Province, China.
Department of Pathology, Yangling Demonstration Zone Hospital, Yangling, Shaanxi Province, China.
Aging (Albany NY). 2018 Oct 25;10(10):2954-2972. doi: 10.18632/aging.101602.
Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can aid in the treatment of numerous diseases in animals. However, natural aging during expansion of ADMSCs prior to their use in transplantation restricts their beneficial effects. Melatonin is reported to exert biorhythm regulation, anti-oxidation, and anti-senescence effects in various animal and cell models. Herein, by using a senescent canine ADMSCs (cADMSCs) cell model subjected to multiple passages , we investigated the effects of melatonin on ADMSCs senescence. We found that melatonin alleviates endoplasmic reticulum stress (ERS) and cell senescence. MT1/MT2 melatonin receptor inhibitor, luzindole, diminished the mRNA expression levels and rhythm expression amplitude of Bmal1 and Nrf2 genes. Nrf2 knockdown blocked the stimulatory effects of melatonin on endoplasmic reticulum-associated degradation (ERAD)-related gene expression and its inhibitory effects on ERS-related gene expression. At the same time, the inhibitory effects of melatonin on the NF-κB signaling pathway and senescence-associated secretory phenotype (SASP) were blocked by Nrf2 knockdown in cADMSCs. Melatonin pretreatment improved the survival of cADMSCs and enhanced the beneficial effects of cADMSCs transplantation in canine acute liver injury. These results indicate that melatonin activates Nrf2 through the MT1/MT2 receptor pathway, stimulates ERAD, inhibits NF-κB and ERS, alleviates cADMSCs senescence, and improves the efficacy of transplanted cADMSCs.
脂肪来源间充质干细胞（ADMSCs）移植可辅助治疗动物的多种疾病。然而，在用于移植之前，ADMSCs扩增过程中的自然老化限制了它们的有益作用。据报道，褪黑素在各种动物和细胞模型中发挥生物节律调节、抗氧化和抗衰老作用。在此，我们使用经过多次传代的衰老犬ADMSCs（cADMSCs）细胞模型，研究了褪黑素对ADMSCs衰老的影响。我们发现褪黑素可减轻内质网应激（ERS）和细胞衰老。褪黑素MT1/MT2受体抑制剂鲁辛朵降低了Bmal1和Nrf2基因的mRNA表达水平和节律表达幅度。Nrf2基因敲低阻断了褪黑素对内质网相关降解（ERAD）相关基因表达的刺激作用及其对ERS相关基因表达的抑制作用。同时，Nrf2基因敲低阻断了褪黑素对cADMSCs中NF-κB信号通路和衰老相关分泌表型（SASP）的抑制作用。褪黑素预处理提高了cADMSCs的存活率，并增强了cADMSCs移植对犬急性肝损伤的有益作用。这些结果表明，褪黑素通过MT1/MT2受体途径激活Nrf2，刺激ERAD，抑制NF-κB和ERS，减轻cADMSCs衰老，并提高移植cADMSCs的疗效。
