Follistain-like 3对滋养细胞与胚胎的影响以及在妊娠并发症发病中的作用

Trophoblast plays an important role in embryonic development and implantation, and the maintenance of normal preganncy, and is also associated with the pathogenesis of pregnancy complications sucha as preeclampsia and gestational diabetes. Previously, we found that serum and placental follistatin-like 3 (FSTL3) was significantly increased in preeclampsia but significantly decreased in gestational diabetes mellitus, suggesting FSTL3 is involved in the pathogenesis of preeclampsia and gestational diabetes possibly via regulating the fuction of trophoblast. Based on the previous findings, with the use of cultured cell lines of trophoblast, in vitro model of embryonic adhesion and in vivo model of embryonic implantation, in combination with siRNA of FSTL3, we will try to observe the regulatory effect of FSTL3 on the function of trophoblast, the adhesion and implantation of embryo, the effect of preeclampsia and gestational diabetes on expression and release of FSTL3 by trophoblast, the effect of FSTL3 on the expression and release of preeclampsia- or gestational diabetes-related factors. The aim of the current investigation was to clarify the the regulatory role of FSTL3 on trophoblast and subsequently on the embryoes, and to expore the possible role in the pathogenesis of pregnancy complications. Our findings will enhance our insight into the regulation of trophoblast and provide potential target of the treatment of preeclampsia.

胎儿来源的滋养细胞在胚胎发育和着床、维持正常妊娠中发挥了重要作用，参与子痫前期等妊娠并发症的发生和发展。在前期研究中，我们发现子痫前期患者血液、胎盘follistatin-like 3（FSTL3）表达显著增高，而妊娠期糖尿病时显著降低，提示FSTL3与、妊娠期并发症的发病有关，其机理可能是通过调控滋养细胞功能，影响胚胎着床和发育，从而影响妊娠结局。因此，我们拟利用体外培养的滋养细胞、胚胎体外粘附和体内着床模型，结合FSTL-3表达调控，阐明FSTL3对胎盘滋养细胞生物学功能的调控效应，观察滋养细胞FSTL3对胚胎粘附、着床和发育的影响，明晰子痫前期和妊娠期糖尿病对滋养细胞FSTL3表达与释放的影响以及滋养细胞FSTL3对子痫前期、妊娠期糖尿病发病相关因子表达与释放的影响。研究结果将丰富滋养细胞和胚胎的调控机制，并为子痫前期等妊娠并发症的防治提供潜在的靶点和治疗策略。

以滋养细胞系SWAN71和JAR为细胞模型，siRNA靶向干扰FSTL3表达，构建了FSTL3调控细胞模型；细胞功能实验证实FSTL3下调显著抑制滋养细胞的增殖、迁移和浸润，并促进细胞凋亡，但不影响滋养细胞上皮-间质转化（EMT）相关上皮标志物（E-cadherin）和间质标志物（Vimentin）表达，揭示了FSTL3对滋养细胞功能的调控效应；体外胚胎黏附实验显示siRNA干扰FSTL3显著抑制滋养细胞球的体外黏附，动物实验显示宫角注射siRNA混合物显著抑制胚胎体内着床，提示滋养细胞FSTL3水平对胚胎黏附和着床有显著影响。为探讨滋养细胞FSTL3与子痫前期、妊娠期糖尿病的关系，我们发现低氧培养诱导滋养细胞FSTL3表达显著上升，而高糖培养导致滋养细胞FSTL3表达显著下降，揭示了FSTL3与子痫前期、妊娠期糖尿病的密切关系，但FSTL3下调不影响滋养细胞子痫前期、妊娠期糖尿病相关因子的表达；FSTL3下调显著抑制滋养细胞的脂肪储积，但不影响相关脂肪转运体的表达，也不影响葡萄糖转运蛋白的表达；因此，FSTL3调节滋养细胞脂肪储积的机制有待进一步研究。