低氧调控的滋养细胞外体lncRNAs对DCs分化及功能的作用研究

The establishment of maternal-fetal tolerance makes great contribution to successful pregnancy, and several factors in the local environment are involved in the modulation of this process. Hypoxia is one of the most unique characteristics of maternal-fetal interface. Trophoblastic cells, which play important roles in the “education” of decidual immune cells such as dendritic cells (DCs), can give response directly to hypoxia signal. However, whether hypoxia can regulate the differentiation and function of DCs by affecting trophoblastic cells is unknown. Long non-coding RNAs (lncRNAs) take part in several important physiological and pathological processes via regulating the expression of target genes. LncRNAs that are packaged in the exosomes secreted by cells can be uptaked by recipient cells and then regulate the function of the latter. We previously got 4 differentiately expressed trophoblastic exosomal lncRNAs (linc-RoR、LEF1-AS1) with hypoxia stimulation. In this study, we will study the effect of trophoblastic exosomal lncRNAs regulated by hypoxia on the differentiation and function of human CD14+ monocytes-derived DCs, and then explore the underlying mechanism through which hypoxia affects the transcription and expression of trophoblastic exosomal lncRNAs from epigenetic level. Our studies will explain the establishment mechanism of maternal-fetal tolerance during implantation from a new perspective, which are hopeful provide novel prevention measures and therapeutic strategies for pathological pregnancy.

母胎界面免疫耐受的建立与维持是妊娠成功的关键，局部微环境中多种因素参与此过程的调控。低氧是妊娠早期母胎界面的特征性微环境之一，滋养细胞不仅能对低氧直接应答，也能对其他免疫细胞如树突状细胞（DCs）进行“驯化”，但低氧是否通过调节滋养细胞影响DCs的分化及功能尚不清楚。长链非编码RNA（lncRNA）通过调控基因表达参与机体多种病理生理过程，可富集在细胞分泌的外体(exosomes)中，传送至受体细胞如免疫细胞等，调节受体细胞功能。我们前期发现滋养细胞exosomes中2个低氧相关差异lncRNAs（linc-RoR、LEF1-AS1）。现拟观察它们对CD14+单核细胞来源的DCs分化及功能的影响，并探讨其作用机制，然后从表观遗传层面研究低氧影响滋养细胞外体lncRNAs表达的转录调控机制。本研究将丰富妊娠植入时母胎免疫耐受建立与维持的机制，同时为复发性自然流产等病理妊娠的防治提供新思路。