目的:反复植入失败(RIF)患者的5-羟色胺稳态异常是否会导致子宫内膜蜕膜化受损?
结论:RIF患者的5-羟色胺稳态异常,伴随着单胺氧化酶(MAO)表达的减少,影响子宫内膜基质细胞的蜕膜化并导致胚胎着床失败。
背景:以前的研究表明,MAO的表达,代谢血清素,RIF患者的子宫内膜减少,5-羟色胺可以诱导大鼠着床的破坏。然而,5-羟色胺稳态异常是否会导致RIF患者的蜕膜化受损,如果是,所涉及的机制,尚不清楚。
■使用来自25名RIF患者和25名可育患者的子宫内膜样本来研究单胺氧化酶A(MAOA)的表达水平,单胺氧化酶B(MAOB),还有血清素.我们分离人子宫内膜基质细胞以研究MAOA的作用,MAOB,和血清素在体外诱导蜕膜化,并使用RNA测序(RNA-seq)和液相色谱-质谱(LC/MS)分析进一步探索了潜在的机制。
方法:采用ELISA和免疫组化方法检测RIF患者子宫内膜5-羟色胺水平,结合单细胞测序数据分析了5-羟色胺代谢异常的关键基因。使用体外人子宫内膜基质细胞诱导的蜕膜化模型和小鼠人工诱导的蜕膜化模型研究了MAOA或MAOB对基质细胞蜕膜化的影响。通过RNA-seq和LC/MS分析探索了MAOA和MAOB调节蜕膜化的潜在机制。
结果:我们发现患有RIF的女性子宫内膜中5-羟色胺代谢异常,子宫内膜基质细胞中MAO减弱。子宫内膜蜕膜化伴随着体内和体外MAO的增加。然而,减弱的MAO导致子宫内膜局部5-羟色胺含量增加,损害基质细胞蜕膜化。RNA-seq和LC/MS分析显示异常的脂质代谢,尤其是磷脂酰胆碱代谢,参与了MAO缺乏引起的蜕膜化缺陷。此外,通过补充磷脂酰胆碱挽救了蜕膜化缺陷。
方法:RNA-seq信息和原始数据可以在NCBIBioproject编号PRJNA892255中找到。
结论:这项研究表明,5-羟色胺代谢稳态受损和MAO表达异常降低是RIF的原因之一。然而,子宫内膜5-羟色胺的来源和其他潜在功能还有待进一步探讨。
结论:这项研究为人子宫内膜蜕膜化中5-羟色胺稳态的机制提供了新的见解,并为RIF患者的治疗提供了新的生物标志物或靶标。
背景:X.盛获得国家自然科学基金(82001629)资助,温州市基本公益研究项目(Y20240030),江苏省自然科学基金项目(BK20200116),和江苏省博士后研究资助(2021K277B)。H.S.由国家自然科学基金(82030040)资助。G.Y.由国家自然科学基金(82171653)资助。作者声明没有利益冲突。
OBJECTIVE: Does abnormal serotonin homeostasis contribute to impaired endometrial decidualization in patients with recurrent implantation failure (RIF)?
CONCLUSIONS: Abnormal serotonin homeostasis in patients with RIF, which is accompanied by decreased monoamine oxidase (MAO) expression, affects the decidualization of endometrial stromal cells and leads to embryo implantation failure.
BACKGROUND: Previous studies have indicated that the expression of MAO, which metabolizes serotonin, is reduced in the endometrium of patients with RIF, and serotonin can induce disruption of implantation in rats. However, whether abnormal serotonin homeostasis leads to impaired decidualization in patients with RIF and, if so, the mechanism involved, remains unclear.
UNASSIGNED: Endometrial samples from 25 patients with RIF and 25 fertile patients were used to investigate the expression levels of monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and serotonin. We isolated human endometrial stromal cells to investigate the role of MAOA, MAOB, and serotonin in inducing decidualization in vitro and further explored the underlying mechanism using RNA-sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC/MS) analyses.
METHODS: The levels of serotonin in the endometrium of patients with RIF were detected by ELISA and immunohistofluorescence, and the key genes involved in abnormal serotonin metabolism were analyzed via combination with single-cell sequencing data. The effects of MAOA or MAOB on the decidualization of stromal cells were investigated using an in vitro human endometrial stromal cell-induced decidualization model and a mouse artificially induced decidualization model. The potential mechanisms by which MAOA and MAOB regulate decidualization were explored by RNA-seq and LC/MS analysis.
RESULTS: We found that women with RIF have abnormal serotonin metabolism in the endometrium and attenuated MAO in endometrial stromal cells. Endometrial decidualization was accompanied by increased MAO in vivo and in vitro. However attenuated MAO caused an increased local serotonin content in the endometrium, impairing stromal cell decidualization. RNA-seq and LC/MS analyses showed that abnormal lipid metabolism, especially phosphatidylcholine metabolism, was involved in the defective decidualization caused by MAO deficiency. Furthermore, decidualization defects were rescued by phosphatidylcholine supplementation.
METHODS: RNA-seq information and raw data can be found at NCBI Bioproject number PRJNA892255.
CONCLUSIONS: This study revealed that impaired serotonin metabolic homeostasis and abnormally reduced MAO expression were among the reasons for RIF. However, the source and other potential functions of serotonin in the endometrium remain to be further explored.
CONCLUSIONS: This study provides new insights into the mechanisms of serotonin homeostasis in human endometrial decidualization and new biomarkers or targets for the treatment of patients with RIF.
BACKGROUND: X. Sheng is supported by grants from the National Natural Science Foundation of China (82001629), the Wenzhou Basic Public Welfare Research Project (Y20240030), the Youth Program of Natural Science Foundation of Jiangsu Province (BK20200116), and Jiangsu Province Postdoctoral Research Funding (2021K277B). H.S. is supported by grants from the National Natural Science Foundation of China (82030040). G.Y. is supported by grants from the National Natural Science Foundation of China (82171653). The authors declare no conflicts of interest.