Abstract

Endometrial dysfunction is an important factor for implantation failure. The function of the endometrium is regulated by multiple factors like sex hormones and circadian rhythms. Endometrial stromal cells (ESCs) are a major cellular component in the endometrium, which is essential for proper physiological activities of the endometrium and the establishment of pregnancy. Melatonin, as a circadian-controlled hormone, plays beneficial roles in the regulation of reproductive processes. MT1, a melatonin receptor, can regulate cell proliferation and apoptosis. Whether melatonin-MT1 signal affects biological function of ESCs remains unknown. Here, we showed that MT1 was expressed in human ESCs (hESCs), which could be regulated by estrogen and progesterone. MT1 knockdown inhibited proliferative activity and promoted apoptosis of hESCs by activating caspase-3 and upregulating the Bax/Bcl2 ratio. Melatonin could reverse the effect of MT1 knockdown on proliferative activity and apoptosis of hESCs. Melatonin could promote proliferative activity of hESCs via the JNK/P38 signal pathway and repress the apoptosis of hESCs via the JNK signal pathway. Moreover, in vivo experiments showed that MT1 expression was decreased in endometrial cells from mice with disrupted circadian rhythm, accompanied by increased apoptosis and suppressed proliferative activity, which could be alleviated by administration of melatonin. These results showed the regulatory effect of melatonin-MT1 signal on biological behaviors of ESCs, which might provide a novel therapeutic strategy for endometrial dysfunction induced by disrupted circadian rhythm.

中文翻译：

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褪黑激素通过MT1调节子宫内膜基质细胞的增殖和凋亡

摘要

子宫内膜功能障碍是植入失败的重要因素。子宫内膜的功能受性激素和昼夜节律等多种因素的调节。子宫内膜基质细胞（ESCs）是子宫内膜的主要细胞成分，对子宫内膜的正常生理活动和妊娠的建立至关重要。褪黑激素作为一种昼夜节律控制的激素，在调节生殖过程中发挥着有益的作用。MT1是一种褪黑激素受体，可以调节细胞增殖和凋亡。褪黑激素-MT1信号是否会影响胚胎干细胞的生物学功能尚不清楚。在这里，我们发现 MT1 在人类胚胎干细胞 (hESCs) 中表达，它可以受雌激素和黄体酮的调节。MT1 敲低通过激活 caspase-3 和上调 Bax/Bcl2 比率来抑制 hESCs 的增殖活性并促进细胞凋亡。褪黑激素可以逆转 MT1 敲低对 hESCs 增殖活性和凋亡的影响。Melatonin可通过JNK/P38信号通路促进hESCs的增殖活性，并通过JNK信号通路抑制hESCs的凋亡。而且，体内实验表明，昼夜节律紊乱的小鼠子宫内膜细胞中 MT1 表达降低，伴随着细胞凋亡增加和增殖活性受到抑制，这可以通过施用褪黑激素来缓解。这些结果表明褪黑激素-MT1信号对胚胎干细胞生物学行为的调节作用，可能为昼夜节律紊乱引起的子宫内膜功能障碍提供一种新的治疗策略。