Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry, CV2 2DX, UK.
Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry, CV2 2DX, UK.
Commun Biol. 2020 Jan 21;3(1):37. doi: 10.1038/s42003-020-0763-1.
During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.
在着床窗口期，子宫内膜准备向妊娠状态转变，这一过程由基质细胞分化为蜕膜细胞（DC）驱动。这个过程的干扰，称为蜕膜化，会导致胎儿-母体界面破裂和流产，但潜在的机制尚不清楚。在这里，我们在体外单细胞水平上重建了蜕膜途径，并证明基质细胞首先会在表现为 DC 或衰老 DC（snDC）之前经历急性应激反应。如果没有免疫细胞介导的 snDC 清除，二次衰老会将 DC 转化为孕激素抵抗细胞，这些细胞大量表达细胞外基质重塑因子。对中期黄体期子宫内膜的额外单细胞分析确定 DIO2 和 SCARA5 为体内蜕膜反应分化的标记基因。最后，我们报告了着床期子宫内膜中促衰老蜕膜反应与反复妊娠丢失之间的显著联系，表明孕前筛查和干预可能会降低流产负担。
