Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
EBioMedicine. 2019 Jun;44:563-573. doi: 10.1016/j.ebiom.2019.05.027. Epub 2019 Jun 11.
Endometrial stromal cell decidualization is critical for embryo implantation. Dysfunctional decidualization leads to implantation failure, miscarriage and even pregnancy associated disorders in subsequent pregnancy trimesters. Protein glycosylation is involved in many physiological and pathological processes. Protein O-fucosyltransferase 1 (poFUT1) is the key enzyme for the O-fucosylation of proteins. However, the role and mechanism of poFUT1 in human endometrial stromal cell decidualization remain elusive.
We employed immunohistochemistry to detect the level of poFUT1 in the uterine endometrium from those of the proliferative phase, secretory phase, early pregnancy women and miscarriage patients. Using human endometrial stromal cells (hESCs) and a mouse model, the underlying mechanisms of poFUT1 in decidualization was investigated.
The level of poFUT1 was increased in the stromal cells of the secretory phase relative to those in the proliferative phase of the menstrual cycle, and decreased in the stromal cells of miscarriage patients compared to women with healthy early pregnancies. Furthermore, we found that poFUT1 promoted hESCs decidualization. The results also demonstrated that poFUT1 increased O-fucosylation on Notch1 in hESCs, which activated Notch1 signaling pathway. Activated Notch1 (NICD), as a specific trans-factor of PRL and IGFBP1 promoters, enhanced PRL and IGFBP1 transcriptional activity, thus inducing hESCs decidualization.
Level of poFUT1 is lower in the uterine endometrium from miscarriage patients than early pregnancy women. poFUT1 is critical in endometrial decidualization by controlling the O-fucosylation on Notch1. Our findings provide a new mechanism perspective on poFUT1 in uterine decidualization that may be a useful diagnostic and therapeutic target for miscarriage. FUND: National Natural Science Foundation of China (31770857, 31670810 and 31870794). Liaoning Provincial Program for Top Discipline of Basic Medical Sciences.
子宫内膜基质细胞的蜕膜化对于胚胎着床至关重要。蜕膜化功能障碍会导致着床失败、流产,甚至在后续妊娠中出现与妊娠相关的疾病。蛋白质糖基化参与了许多生理和病理过程。蛋白 O-岩藻糖基转移酶 1(poFUT1)是蛋白质 O-岩藻糖基化的关键酶。然而,poFUT1 在人子宫内膜基质细胞蜕膜化中的作用和机制仍不清楚。
我们采用免疫组织化学方法检测了增殖期、分泌期、早孕妇女和流产患者子宫子宫内膜中 poFUT1 的水平。利用人子宫内膜基质细胞(hESCs)和小鼠模型,研究了 poFUT1 在蜕膜化中的潜在机制。
与月经周期的增殖期相比,poFUT1 在分泌期基质细胞中的水平增加,而与健康早孕妇女相比,流产患者基质细胞中的 poFUT1 水平降低。此外,我们发现 poFUT1 促进了 hESCs 的蜕膜化。结果还表明,poFUT1 增加了 hESCs 中 Notch1 的 O-岩藻糖基化,从而激活了 Notch1 信号通路。激活的 Notch1(NICD)作为 PRL 和 IGFBP1 启动子的特异性转录因子,增强了 PRL 和 IGFBP1 的转录活性,从而诱导 hESCs 的蜕膜化。
流产患者子宫子宫内膜中的 poFUT1 水平低于早孕妇女。poFUT1 通过控制 Notch1 的 O-岩藻糖基化在子宫内膜蜕膜化中起关键作用。我们的研究结果为 poFUT1 在子宫蜕膜化中的作用提供了一个新的机制视角,可能成为流产的一种有用的诊断和治疗靶点。
国家自然科学基金(31770857、31670810 和 31870794)。辽宁省基础医学重点学科项目。