Extracellular vesicles-derived lncRNA SNHG12 maintains normal pregnancy by regulating p-STAT3/G-CSF axis to mediate the crosstalk between trophoblast and macrophage.

The crosstalk between trophoblasts and macrophages at the maternal-fetal interface is critical for the establishment and maintenance of normal pregnancy. Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication, facilitating the exchange of biological signals between trophoblasts and macrophages. In this study, trophoblasts-derived EVs (Tro-Evs) were isolated by ultracentrifugation and characterized using nanoparticle tracking analysis, transmission electron microscopy and western blot. LncRNA sequencing revealed distinct lncRNAs profiles in macrophages treated with Tro-Evs, with lncRNA SNHG12 identified as a pivotal regulator. Functional assays, including RT-PCR, western blot, elisa and flow cytometry demonstrated that Tro-EVs-derived lncRNA SNHG12 induces M2 macrophage polarization. Mechanistically, lncRNA SNHG12 directly interacts with STAT3 to modulate its phosphorylation, thereby enhancing M2 macrophage polarization and activating STAT3-mediated transcription of G-CSF. Moreover, G-CSF secreted by M2 macrophages reciprocally enhance the migration and invasion of trophoblasts, establishing a positive-feedback manner. Clinically, lncRNA SNHG12 expression is down-regulated in the villous tissues from patients with recurrent spontaneous abortion compared with normal women. Finally, preclinical study demonstrated that lncRNA SNHG12 improves the embryo absorption of mice in vivo. Our findings highlight the critical role of Tro-EVs-transferred SNHG12 in intercellular communication of trophoblasts and macrophages, illuminating a novel mechanism underlying the establishment and maintenance of normal pregnancy.