胎盘发育不良与蜕膜化障碍致早期妊娠失败的分子机制及其干预研究

The maternal-fetal cross-talk and mutual adaptation are essential for the establishing and sustaining of a successful pregnancy, during which the decidualization of endometrium and the normal development of placenta are two keyfactors. Failure in decidualization or malformation of placenta would lead to pregnancy failure including miscarriage. Miscarriage is a common disease but lacks effective strategies for prevention and treatment. Our previous study reveals that the cross-talk between the embryonic trophoblasts and maternal decidual immune cells and stromal cells helps to modulate the progression of decidualization and placenta development, while the dysregulation of the cross-talk would cause pregnancy failure. In this project we focus on the key events during the course of pregnancy (endometrium decidualization and placenta development), and utilize human clinical samples, mouse models and techniques of omics, bioinformatics, cellular and molecular biology and immunology, to systematically study in vivo, in vitro and ex vivo how the cells at the maternal-fetal interface regulate the progression of decidualization and placenta development, and to elucidate how the dysregulation causes failure in decidualization and placenta development and further leads to pregnancy failure. We hope to demonstrate the importance of maternal-fetal cross-talk from physiological, pathological and molecular perspectives, and hope to see it transferred to clinical strategies for the diagnosis and treatment of pregnancy failure and complications, in order to improve health for both mother and fetus.

正常妊娠的建立和维持依赖母-胎之间的互作与适应，其中子宫内膜蜕膜化与胎盘的正常发育是其关键。一旦蜕膜化进展障碍、胎盘形成不良将导致妊娠失败如自然流产。自然流产发病率高，缺乏有效防治策略。我们前期研究发现：母-胎界面滋养细胞与蜕膜免疫细胞和蜕膜基质细胞协调对话调控子宫蜕膜化进程与胎盘正常发育，母-胎对话失调将导致妊娠失败，本项目围绕妊娠过程的关键生物学事件（子宫内膜蜕膜化与胎盘发育），利用人体标本与小鼠模型，通过组学筛选与信息学分析、一系列细胞与分子生物学、免疫学技术，从体内、体外、ex vivo系统研究母-胎界面功能细胞协作调控子宫内膜蜕膜化进程与胎盘发育过程，并解析异常调控引发胎盘发育不良与蜕膜化障碍的分子机制，进一步探讨母-胎异常对话致妊娠失败的分子机制，从生理与病理方面阐述母-胎对话在妊娠中的关键作用，并探索妊娠失败与妊娠并发症的早期预警与干预策略，以期改善母婴健康。

正常妊娠的建立和维持依赖母-胎之间的互作与适应，其中子宫内膜蜕膜化与胎盘的正常发育是其关键。一旦蜕膜化进展障碍、胎盘形成不良将导致早期妊娠失败或中晚期妊娠并发症。利用人体标本与小鼠模型，通过组学筛选与信息学分析、一系列细胞与分子生物学、免疫学技术，从体内、体外、ex vivo系统研究了：1）免疫细胞与滋养细胞互作异常致胎盘发育不良与妊娠失败的分子机制，如滋养细胞通过分泌趋化因子CXCL2募集外周NK到达母胎界面，并进一步训导形成CXCR4+与CXCR4-CD56brightNK，CXCR4+CD56brightNK作为母胎界面IL-4的主要来源，诱导Th2型优势与母胎耐受，促进成功妊娠；滋养细胞通过HLA-G依赖的诱导免疫检查点信号分子PD-1、Tim-3、CTLA-4的表达，与免疫细胞（T、NK）耐受表型；滋养细胞在不良刺激下产生Gal-9与蜕膜CD11chigh巨噬细胞的互作致子痫前期。2）免疫细胞与蜕膜基质细胞互作异常致蜕膜化障碍与妊娠失败的分子机制：探讨了蜕膜化调控机制，发现蜕膜化关键的转录因子TORC2；蜕膜基质细胞及其蜕膜化分泌cAMP通过PKA-CREB介导的CD56在NK细胞上调，促进蜕膜NK细胞的耐受与血管重塑功能；蜕膜化调控异常致妊娠失败机制，高脂等不良刺激可通过棕榈酰化修饰抑制蜕膜化致妊娠失败；子宫内膜MSC与巨噬细胞互作诱导母胎耐受与正常妊娠。3）发现了一个新的NK亚群—Tim-3+NK，在早孕期特异升高，具有耐受表型，用于早期妊娠失败的病因筛查于预后预测；Gal-9在PE患者孕中期的显著升高可以预测PE发生。这一系利研究不仅解释了母胎界面功能细胞（滋养细胞、基质细胞、免疫细胞亚群）间的协调互作及其在妊娠建立和维持中的作用，为早期妊娠失败与晚期子痫前期的预警与干预提供了新的策略。