内分泌-免疫调节失常诱发蜕膜化障碍与母-胎免疫紊乱致妊娠失败的机制研究

The normal function of maternal endocrine-immunoregulation is essential for a successful pregnancy, during which the decidualization of endometrium and the establishing of maternal-fetal immunotolerance are the key factors. While the decidualization process is blocked or the maternal-fetal immunoregulation is impaired, it will lead to pregnancy loss. Our previous studies reveal that several important factors (such as TSLP, COX-2 and miR-184) from the endocrine-immunoregulatory network in early pregnancy help to modulate the progression of decidualization and maternal-fetal immunotolerance by coordinating the cross-talk between the embryonic trophoblasts, maternal decidual stromal cells and immune cells. Dysregulation at any step will result in pregnancy loss, but the detailed mechanisms are still largely unknown. Based on the key scientific question “what it is the underlying mechanism of endocrine-immunoregulation in the establishing and sustaining of pregnancy?”, we focus on the critical events during the course of pregnancy (endometrium decidualization and maternal-fetal immunotolerance), and utilize human clinical samples and disease models as well as multiple techniques (such as genome-wide screening, bioinformatic analyses, immunotechnique etc.), to systematically study the molecular mechanisms of how the endocrine-immunoregulation network regulates decidualization and maternal-fetal immunotolerance, and to elucidate the pathological mechanisms of how the aberrant endocrine-immunoregulation network causes poor decidualization and disorder of maternal-fetal immunoregulation and further leads to pregnancy loss. The early warning indicators for failure pregnancy may be figured out in this study. It is promising to provide scientific evidences for the prevention and therapy of early pregnancy failure, in order to improve health for both mothers and infants.

成功妊娠依赖于母体内分泌-免疫调节功能的正常发挥，其中子宫蜕膜化和母-胎免疫耐受的建立是关键。一旦蜕膜化进程受阻、母-胎免疫调节紊乱将导致妊娠失败。我们前期研究发现，早孕期内分泌-免疫调节网络中一些关键分子（如TSLP, COX-2和miR-184）可通过协调滋养细胞、蜕膜基质细胞和免疫细胞间互作调控蜕膜化和母-胎免疫，任一环节障碍将可能诱发妊娠失败，但具体机制不明。本项目针对“妊娠建立和维持的内分泌-免疫调节机制”这一关键科学问题，以母-胎交互对话为核心，围绕妊娠过程关键生物学事件（蜕膜化和母-胎免疫耐受），借助临床标本和疾病模型，通过组学筛选与信息学分析、免疫学技术等，系统探讨内分泌-免疫调节功能协作调控蜕膜化和母-胎免疫耐受的分子机制，解析失常调控引发蜕膜化障碍与母-胎免疫紊乱导致妊娠失败的病理机制，并探索妊娠失败的早期预警指标。有望为防治早期妊娠失败提供科学依据，以期改善母婴健康。

成功妊娠依赖于母体内分泌-免疫调节功能的正常发挥，其中子宫蜕膜化和母-胎免疫耐受的建立是关键。一旦蜕膜化进程受阻、母-胎免疫调节紊乱将导致妊娠失败。本项目围绕母胎界面免疫细胞与基质细胞、滋养细胞互作异常，引发蜕膜化不良和母-胎免疫调节紊乱进而导致妊娠失败开展了机制研究。本研究的重要发现有：(1)蜕膜化过程中1,6-二磷酸果糖（FBP）累积，FBP通过细胞因子IL-27调控COX-2+ M2-like巨噬细胞的分化；(2)蜕膜化过程中谷氨酰胺代谢通路被激活，而反复自然流产（RSA）患者的内膜基质细胞体外诱导蜕膜化异常并且谷氨酰胺代谢通路受阻，通过补充下游代谢物α-酮戊二酸可恢复受损的蜕膜化；(3)琥珀酸代谢关键酶编码基因SDHB在孕早期因启动子区高甲基化而转录沉默，导致SDHB蛋白量降低及其底物琥珀酸的累积，高水平的琥珀酸可抑制细胞羟基化酶PHD的活性，从而激活细胞低氧诱导因子HIF信号，促进滋养细胞的侵袭能力，保障胚胎着床的顺利进行；(4)鉴定了滋养细胞RNA m1A 、m6A修饰图谱及调控因子YTHDF3、ALKBH5，并揭示滋养细胞细胞应对低氧应答的潜在机制；(5)蛋白质L-精氨酸甲基转移酶3（PRMT3）在蜕膜巨噬细胞中表达增加，会促进一氧化氮合酶内源抑制剂ADMA的产生，进而降低了NO的浓度，诱导了滋养层细胞凋亡，与RSA发生相关；(6) 我们利用人类母体组织和小鼠模型揭示了组氨酸-组胺代谢通量亢进对流产的影响。组氨酸血清水平与其他孕前生物标志物一起，可以通过我们建立的AI-MP模型精确预测即将怀孕的流产风险。为了促进我们的模型的广泛验证，从而促进其转化应用，我们开发了一个基于训练有素的AI-MP的流产预测的互动平台。本项目的研究结果为制订防治早期妊娠失败的新策略提供了科学依据，以期改善母婴健康。