蜕膜基质细胞调控髓系抑制细胞表型和功能的分子机制

The molecular mechanism of maternal-fetal immune tolerance formation is still unclear. It is of great theoretical and practical significance to reveal this mechanism in depth. Our previous studies have demonstrated that myeloid suppressor cells (MDSCs) exist in the decidua and the number of them will change dynamically at different periods of pregnancy. Decidual MDSCs consistently maintain unique undifferentiated myeloid phenotype and immunosuppressive function in the maternal fetal interface and participate in the formation of maternal fetal immune tolerance. However, the molecular mechanism of the generation and maintenance of this characteristic of decidual MDSCs remains unclear. Our preliminary study found that decidual stromal cells (DSCs) can induce decidual MDSCs continuously express undifferentiated myeloid phenotype and immunosuppressive molecules in high level. In view of this, we hypothesized that DSCs are likely to be the key cells regulating phenotype and function of decidual MDSCs. To verify this hypothesis, we will carry out further research taking cross talk between DSCs and MDSCs as a starting point, on the basis of previous studies, using appropriate animal models and clinical samples to further reveal the molecular mechanism of DSCs regulating the maintenance of undifferentiated myeloid phenotype and immunosuppressive function of decidual MDSCs and explore the feasibility of recurrent spontaneous abortion treatment with MDSCs as a target.

迄今为止，母胎免疫耐受格局形成的分子机制尚不清楚。深入揭示这一机制具有重要的理论和实践意义。我们前期研究已经明确蜕膜中存在髓系抑制细胞（MDSCs），且其数量在妊娠不同时期会发生动态变化。MDSCs在母胎界面始终维持独特的未分化髓系表型并发挥免疫抑制功能，参与母胎免疫耐受格局的形成。蜕膜MDSCs这种特性产生和维持的分子机制尚不清楚。我们的初步研究发现，蜕膜基质细胞（DSCs）可诱导蜕膜MDSCs 持续高表达未分化髓系表型和免疫抑制分子。因此，我们提出如下假说：DSCs很可能是调控蜕膜MDSCs表型和功能的关键细胞。为了验证这一假说，本项目拟在前期研究的基础上，利用适当的模式生物和临床标本，以DSCs和蜕膜MDSCs交互对话为切入点进一步开展研究，以期深入揭示DSCs调控蜕膜MDSCs维持未分化髓系表型及免疫抑制功能的分子机制，同时探索以MDSCs为靶点的复发性流产治疗方法的可行性。

母胎界面免疫耐受调控是生殖医学的重要问题，母胎界面免疫调节失衡与不明原因妊娠丢失（unexplained recurrent pregnancy loss,URPL）等不良妊娠结局密切相关。与外周血相比，母胎界面免疫细胞具有独特的表型及功能特征，探究母胎界面免疫细胞的诱导分化及调控机制对阐明母胎免疫耐受机制至关重要。本课题首次研究并明确了早孕期蜕膜多形核髓系抑制细胞（polymorphonuclear myeloid-derived suppressor cells,PMN-MDSCs）的脂质相关表达特征，证明早孕期蜕膜PMN-MDSCs比例与PMN-MDSCs脂质水平存在正相关。发现脂肪酸代谢途径在调控蜕膜PMN-MDSCs分化中的重要作用，并证明了蜕膜微环境中IL6是促进蜕膜PMN-MDSCs分化的关键分子，蜕膜来源IL6可通过pSTAT3/FABP5/PGE2通路诱导PMN-MDSCs分化和免疫抑制特征的形成。证明URPL患者外周血中性粒细胞脂肪酸转运蛋白FABP5低表达可能是URPL患者蜕膜PMN-MDSCs分化不足的原因之一。这些研究成果为靶向脂代谢治疗URPL等疾病提供理论依据。