Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
FASEB J. 2019 Jan;33(1):314-326. doi: 10.1096/fj.201800124R. Epub 2018 Jul 6.
Migration of placental extravillous trophoblast (EVT) cells into uterine decidua facilitates the establishment of blood circulation between mother and fetus and is modulated by EVT-decidual cell interaction. Poor or excessive EVT migration is associated with pregnancy complications such as preeclampsia or placenta accreta. Glial cells missing 1 (GCM1) transcription factor is essential for placental development, and decreased GCM1 activity is detected in preeclampsia. To study whether GCM1 regulates trophoblast cell migration, here we showed that GCM1 promotes BeWo and JAR trophoblast cell migration through a novel target gene, WNT10B. Moreover, WNT10B signaling stimulated cytoskeletal remodeling via Rac1 and frizzled 7 (FZD7) was identified as the cognate receptor for WNT10B to up-regulate cell migration. We further showed that secreted frizzled-related protein 3 (SFRP3) is expressed in uterine decidual cells by immunohistochemistry and that SFRP3 expression in telomerase-transformed human endometrial stromal cells (T-HESCs) is elevated under decidualization stimuli and further enhanced by bone morphogenetic protein 2 via SMAD1. SFRP3 blocked the interaction between FZD7 and WNT10B to decrease BeWo cell migration, which corroborated the elevated BeWo cell migration when cocultured with decidualized and SFRP3-knockdown T-HESC monolayer. Our results suggest that GCM1 up-regulates EVT cell migration through WNT10B and FZD7, which is negatively modulated by decidual SFRP3.-Wang, L.-J., Lo, H.-F., Lin, C.-F., Ng, P.-S., Wu, Y.-H., Lee, Y.-S., Cheong, M.-L., Chen, H. SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis.
胎盘绒毛外滋养细胞（EVT）向子宫蜕膜的迁移促进了母婴之间血液循环的建立，并受 EVT-蜕膜细胞相互作用的调节。EVT 迁移不良或过度与子痫前期或胎盘附着异常等妊娠并发症有关。胶质细胞缺失 1（GCM1）转录因子对胎盘发育至关重要，子痫前期检测到 GCM1 活性降低。为了研究 GCM1 是否调节滋养细胞迁移，我们在这里表明，GCM1 通过新的靶基因 WNT10B 促进 BeWo 和 JAR 滋养细胞迁移。此外，WNT10B 信号通过 Rac1 刺激细胞骨架重塑，并且发现 frizzled 7（FZD7）是 WNT10B 的同源受体，可上调细胞迁移。我们进一步表明，免疫组织化学显示，分泌型卷曲相关蛋白 3（SFRP3）在子宫蜕膜细胞中表达，端粒酶转化的人子宫内膜基质细胞（T-HESCs）在蜕膜化刺激下表达升高，并通过 SMAD1 进一步增强骨形态发生蛋白 2。SFRP3 阻断了 FZD7 和 WNT10B 之间的相互作用，从而减少了 BeWo 细胞的迁移，这与与蜕膜化和 SFRP3 敲低的 T-HESC 单层共培养时 BeWo 细胞迁移增加相符。我们的结果表明，GCM1 通过 WNT10B 和 FZD7 上调 EVT 细胞迁移，而 SFRP3 下调则由蜕膜负调节。
