State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences.
Department of Obstetrics and Gynaecology, Peking University First Hospital.
J Hypertens. 2018 Nov;36(11):2215-2225. doi: 10.1097/HJH.0000000000001808.
The signalling of the receptor tyrosine kinase Met is critical in promoting trophoblast cell invasion, and the deficiency in HGF/Met signalling is associated with preeclampsia. The semaphorin family member semaphorin4D (sema4D) and its receptor Plexin-B1 have been reported to control tumour cell invasion by coupling with Met. We hypothesized that sema4D/Plexin-B1 may promote trophoblast invasion by activating Met, and downregulation of sema4D/Plexin-B1 may account for the deficiency in Met signalling in preeclamptic placenta.
In this study, Met and Erk activation and the expression of sema4D/Plexin-B1 in normal and preeclamptic placentas were comparably measured. The role of sema4D in trophoblast cell invasion and tubulogenesis was examined in vitro using the Transwell invasion assay and tube formation assay in trophoblast-endothelial cell co-culture model.
Met, sema4D and Plexin-B1 co-localized in various subtypes of human trophoblast cells, including villous trophoblasts and extravillous trophoblasts (EVTs). In early-onset preeclampsia (E-PE) placentas, the phosphorylated Met and Erk as well as sema4D and Plexin-B1 were much lower than those in gestational week-matched preterm-labour (PTL) placentas. In human trophoblast HTR8/SVneo cell line, sema4D could promote Met and Erk phosphorylation as well as enhance trophoblast cell invasion and tubulogenesis with endothelial cells. Moreover, the effect of sema4D on HTR8/SVneo could be blocked by knocking down Met with specific siRNA.
The crosstalk between sema4D and Met could transactivate Met to promote trophoblast cell invasion and differentiation, and decreased expression of sema4D and Plexin-B1 may be responsible for the deficiency in Met signalling and the development of preeclampsia.
受体酪氨酸激酶 Met 的信号转导对于促进滋养细胞浸润至关重要，而 HGF/Met 信号转导的缺失与子痫前期有关。信号蛋白家族成员 semaphorin4D（sema4D）及其受体 Plexin-B1 已被报道通过与 Met 偶联来控制肿瘤细胞浸润。我们假设 sema4D/Plexin-B1 可能通过激活 Met 促进滋养细胞浸润，而子痫前期胎盘中 Met 信号转导的缺失可能与 sema4D/Plexin-B1 的下调有关。
本研究比较了正常和子痫前期胎盘中转录因子 Met 和 Erk 的激活以及 sema4D/Plexin-B1 的表达情况。在滋养细胞-内皮细胞共培养模型中，使用 Transwell 侵袭实验和管形成实验体外研究了 sema4D 在滋养细胞侵袭和管状形成中的作用。
Met、sema4D 和 Plexin-B1 共同定位于各种人类滋养细胞亚型中，包括绒毛滋养细胞和绒毛外滋养细胞（EVT）。在早发型子痫前期（E-PE）胎盘中，磷酸化 Met 和 Erk 以及 sema4D 和 Plexin-B1 的表达明显低于孕龄匹配的早产（PTL）胎盘。在人滋养细胞 HTR8/SVneo 细胞系中，sema4D 可以促进 Met 和 Erk 磷酸化，并增强滋养细胞与内皮细胞的侵袭和管状形成。此外，特异性 siRNA 敲低 Met 可以阻断 sema4D 对 HTR8/SVneo 的作用。
sema4D 与 Met 之间的串扰可以转激活 Met 促进滋养细胞浸润和分化，而 sema4D 和 Plexin-B1 的表达下调可能是 Met 信号转导缺失和子痫前期发展的原因。
