Zeng Shanshan, Liang Yingyu, Lai Siying, Bi Shilei, Huang Lijun, Li Yulian, Deng Weinan, Xu Pei, Liu Mingxing, Xiong Zhongtang, Chen Jingsi, Tu Zhaowei, Chen Dunjin, Du Lili
Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
J Reprod Immunol. 2023 Feb;155:103776. doi: 10.1016/j.jri.2022.103776. Epub 2022 Nov 24.
Defects in decidual response are associated with adverse pregnancy outcomes which includes recurrent pregnancy loss (RPL). It is reported that cellular senescence happens during decidualization and pro-senescent decidual response in the luteal phase endometrium is related to RPL. However, the underlying mechanisms of how excessive decidual senescence takes place in RPL decidua cells remain largely unexplored. The senescent phenotype of RPL decidua and tumor necrosis factor receptor 1(TNFR1) expression were analyzed by using our previously published single-cell sequencing dataset of decidua cells from 6 RPL and 5 matched normal decidua, which were further verified by PCR and WB in decidual tissues. Effects of TNFα on the decidual stromal cells (DSCs) senescence and underlying molecular pathways were analyzed using the in vitro decidualization model of human endometrial stromal cells (HESCs). We showed that decidual stroma cells from RPL patients exhibited transcriptomic features of cellular senescence by analysis of single-cell datasets. The TNFα level and TNFR1 expression were increased in RPL decidua tissues. Furthermore, in vitro cell model demonstrated that increased TNFα induced excessive senescence during decidualization and TNFR1/p53/p16 pathway mediates TNFα-induced stromal senescence. In addition, we also found that the expression of IGFBP1 was regulated by TNFα-TNFR1 interaction during decidualization. Taken together, the present findings suggest that the increased secretion of TNFα induced stromal cell excessive senescence in RPL decidua, which is mediated via TNFR1, and thus provide a possible therapeutic target for the treatment of RPL.
蜕膜反应缺陷与不良妊娠结局相关，其中包括复发性流产（RPL）。据报道，细胞衰老发生在蜕膜化过程中，黄体期子宫内膜中促衰老的蜕膜反应与复发性流产有关。然而，RPL蜕膜细胞中蜕膜过度衰老发生的潜在机制在很大程度上仍未得到探索。通过使用我们之前发表的来自6例RPL患者和5例匹配的正常蜕膜的蜕膜细胞单细胞测序数据集，分析了RPL蜕膜的衰老表型和肿瘤坏死因子受体1（TNFR1）表达，并在蜕膜组织中通过PCR和WB进一步验证。使用人子宫内膜基质细胞（HESC）的体外蜕膜化模型，分析了TNFα对蜕膜基质细胞（DSC）衰老及潜在分子途径的影响。我们通过单细胞数据集分析表明，RPL患者的蜕膜基质细胞表现出细胞衰老的转录组特征。RPL蜕膜组织中TNFα水平和TNFR1表达增加。此外，体外细胞模型表明，TNFα增加诱导蜕膜化过程中的过度衰老，且TNFR1/p53/p16途径介导TNFα诱导的基质衰老。此外，我们还发现，在蜕膜化过程中，IGFBP1的表达受TNFα-TNFR1相互作用的调节。综上所述，目前的研究结果表明，TNFα分泌增加诱导RPL蜕膜中的基质细胞过度衰老，这是通过TNFR1介导的，从而为RPL的治疗提供了一个可能的治疗靶点。
