髓系抑制细胞与滋养细胞的交互对话及其分子机制

The establishment and maintenance of normal pregnancy depends on the maternal-fetal immune tolerance. Furthermore, the coordination of maternal-fetal interactive dialogue is the key to the formation of this immunotolerance. Our previous study found that MDSCs, existing in the decidual tissue, is a new kind of cell subsets in addition to NK cells, T cells, macrophages and other classic decidual immune cells. Moreover，granulocytic MDSCs can have interactive dialogue with Treg cells and exert immunosuppressive function to maintain the maternal fetal immune tolerance. Meanwhile, we also found that granulocytic MDSCs can promote the migration of vascular endothelial cells. Accordingly, we hypothesize that MDSCs and trophoblasts may have interactive dialogue and involve in the formation of maternal-fetal immune tolerance in this subject. Therefore, this study will reveal the effect of MDSCs on the proliferation and invasion of trophoblasts and explore the role of trophoblasts in the enrichment, phenotypic differentiation and functional regulation of MDSCs, using the mouse model of spontaneous abortion and clinical tissue specimens via adopting multiple methods such as microarray, siRNA, adoptive transfer and etc. Meanwhile, we will develop intervention treatment targeting MDSCs. The expected results will disclose the mechanism of cross talk between MDSCs and trophoblasts at the maternal fetal interface, which can provide a scientific basis for exploring new diagnostic and therapeutic methods of unexplained recurrent spontaneous abortion.

正常妊娠的建立和维持依赖于母胎免疫耐受，而协调的母胎交互对话是这种耐受形成的关键。我们前期研究发现髓系抑制细胞(MDSCs)存在于蜕膜局部组织中，是除了NK细胞、T细胞、巨噬细胞等经典蜕膜免疫细胞之外的一种新的细胞亚群，并发现粒系MDSCs可与Treg细胞进行交互对话，发挥免疫抑制功能而维持母胎免疫耐受，同时，我们还发现粒系MDSCs可促进血管内皮细胞迁移。鉴于此，在本课题中我们提出蜕膜MDSCs与滋养细胞可能存在交叉对话，参与母胎免疫耐受形成的假说。本项目拟采用自然流产小鼠模型和临床组织标本，采用microarray、siRNA 、过继转输等方法，解析MDSCs对滋养细胞增殖、侵袭生物学行为的影响及滋养细胞对MDSCs的募集、表型分化及功能调控机制，开展以MDSCs为靶点的干预治疗，预期结果将揭示母胎界面MDSCs和滋养细胞交互对话的机制，为不明原因复发性流产防治措施的探索提供科学依据。

正常妊娠的建立和维持依赖于母胎免疫耐受，母胎界面细胞间精密的交互对话是母胎免疫耐受形成的基础，而交互对话异常将导致复发性自然流产（RPL）等妊娠并发症。我们前期研究发现蜕膜髓系抑制细胞（MDSCs）是妊娠免疫调节网络重要组成部分，我们在本课题中采用适当的动物模型和临床组织标本探索了MDSCs细胞表型功能特征及其诱导分化的分子机制。发现正常早孕期蜕膜CD33+CD11b+HLA-DR-/low MDSCs比例显著高于RPL患者，且增高的亚型主要为CD15+ 多形核MDSCs（PMN-MDSCs）；滋养细胞分泌CXCL12激活MDSCs中JNK信号通路及PI3-K/Akt通路，上调MDSCs中 CXCR4的表达，募集MDSCs至母胎界面并诱导MDSCs获得并维持免疫抑制功能。母胎界面MDSCs参与滋养细胞向绒毛外滋养细胞（EVT）途径分化。而正常早孕与RPL患者PMN-MDSCs存在差异表达基因及通路。人正常早孕与RPL患者蜕膜PMN-MDSCs在凋亡通路存在激活，蜕膜TRAIL高表达以及PMN-MDSCs表面DcR2下调介导RPL患者蜕膜PMN-MDSCs的凋亡过度激活是导致RPL患者蜕膜中PMN-MDSCs数量减少的分子机制之一。蜕膜基质细胞通过调节EVT的STAT1/3/5磷酸化水平进而调控其增殖及侵袭能力。本项目首次证明母胎界面PMN-MDSCs是一群成熟的、激活的粒系细胞，由外周血中性粒细胞诱导分化而来，母胎界面微环境通过GM-CSF/pSTAT5/PD-L2通路诱导中性粒细胞向PMN-MDSCs分化。我们的研究具有较强的创新性以及临床转化价值，明确了母胎界面MDSCs特征、来源、功能及细胞命运，为靶向MDSCs防治复发性自然流产提供理论依据。