外泌体源LncRNA SNHG12/STAT3/G-CSF轴通过介导滋养细胞与巨噬细胞的交互对话维持正常妊娠的机制研究

正常妊娠的建立与维持需要母胎交互对话的精准调控。新近研究表明，外泌体作为一种细胞间通讯的重要媒介，在母胎界面细胞交互对话中扮演着重要角色。申请人前期研究发现，母胎界面M1型巨噬细胞可通过分泌外泌体抑制滋养细胞的侵袭和迁移，参与复发性流产的发生。然而，关于滋养细胞来源的外泌体对巨噬细胞极化的影响仍未明确。基于此，申请人通过高通量测序结合细胞学预实验发现，滋养细胞来源的外泌体可通过传递LncRNA SNHG12促进巨噬细胞M2型极化，建立滋养细胞和M2型巨噬细胞的互作网络，介导正常妊娠维持；进一步机制研究提示，LncRNA SNHG12的上述作用可能通过调控STAT3蛋白的磷酸化进而促进G-CSF的转录实现。在此基础上，本项目拟通过体内、外实验及临床样本验证，系统阐明外泌体LncRNA SNHG12/STAT3/G-CSF轴的调控机制，以期为妊娠并发症的诊治提供新的有效靶点。

The establishment and maintenance of pregnancy requires the precise regulation of maternal-fetal interaction. Exosomes, as the important medium for cell-to-cell communication, play important roles in cell-interaction at the maternal-fetal interface. Our previous study found that M1 macrophages could inhibit the invasion and migration of trophoblasts by secreting exosomes, participating in the occurrence of recurrent spontaneous miscarriage. However, the effect of trophoblast-derived exosomes on the polarization of macrophages is still unclear. Based on this, by high-throughput sequencing combined with cytology pre-experiments, we found that trophoblast-derived exosomes can promote M2 macrophages polarization by delivering LncRNA SNHG12, thereby establishing the interaction network between trophoblasts and M2-type macrophages to mediate normal pregnancy. Further mechanistic studies suggest that the above-mentioned effects of LncRNA SNHG12 might be achieved by regulating the phosphorylation of STAT3 protein to promote the transcription of G-CSF. On this basis, we intend to systematically clarify the regulatory mechanism of the exosomal LncRNA SNHG12/STAT3/G-CSF axis through in vivo, in vitro experiments and clinical sample analysis, hoping to provide new effective targets for the diagnosis and treatment of pregnancy complications.