Extravillous trophoblast invasion accelerated by WNT3A, 5A, and 10B via CD44
Extravillous trophoblast invasion accelerated by WNT3A, 5A, and 10B via CD44
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DOI：
10.1080/14767058.2019.1684891
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发表时间：
2019-11-14
影响因子：
1.8
通讯作者：
Takizawa, Toshihiro
中科院分区：
文献类型：
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作者：
Takahashi, Hironori;Ogoyama, Manabu;Takizawa, Toshihiro
适当的胞外滋养细胞（EVT）侵袭对妊娠成功至关重要。之前，我们发现EVT表达CD44，加速了EVT的侵袭。然而，其通过CD44的调控机制尚不清楚。我们的假设是WNT信号通过CD44增强EVT侵袭。为了验证这一假设，我们利用EVT细胞系和分离的原代EVT研究了WNT配体对CD44表达和EVT侵袭的影响。方法：采用EVT细胞系（HTR8/SVneo和HChEpC1b），从妊娠早期滋养细胞中分离原代EVT。细胞中分别添加WNT3A、5A和10B。我们检测了细胞侵袭和CD44和基质金属蛋白酶（MMP） 9的表达。接下来，为了阐明WNT10B在evt中的通路，我们使用siRNA敲除WNT10B，并使用添加了WNT10B的激活剂（氯化锂）或抑制剂（FH535, XAV939）激活或抑制WNT经典通路。结果：WNT3A、5A和10B加速了EVT细胞系的侵袭，分离了原发EVT。WNT配体也上调了CD44和MMP9的表达。WNT10B敲低显著抑制EVT侵袭，同时抑制CD44的表达。WNT经典通路激活因子上调CD44表达，其抑制剂在加入WNT10B后下调CD44表达。结论：本研究首次证实了WNT3A、WNT5A和WNT10B可能存在于evt CD44上游。其中，WNT10B可能是EVT侵袭的新型加速器。多种WNT配体介导的WNT信号可能参与EVT侵袭。
Introduction: Appropriate extravillous trophoblast (EVT) invasion is essential for successful pregnancy. Previously, we showed that EVTs express CD44, which accelerated EVT invasion. However, its regulation mechanism via CD44 remains unknown. Our hypothesis was that WNT signaling enhanced EVT invasion via CD44. To test this hypothesis, we investigated the effects of WNT ligands on CD44 expression and EVT invasion using EVT cell lines and isolated primary EVTs. Methods: We used EVT cell lines (HTR8/SVneo and HChEpC1b) and isolated primary EVTs, extracted from first-trimester trophoblasts. The cells were supplemented with WNT3A, 5A, and 10B. We examined cell invasion and the expressions of CD44 and matrix metalloproteinase (MMP) 9. Next, to clarify the pathway of WNT10B in EVTs, we knock-downed WNT10B using siRNA and activated or inhibited the WNT canonical pathway using an activator (lithium chloride) or inhibitor (FH535, XAV939) with WNT10B addition. Results: WNT3A, 5A, and 10B accelerated the invasion in the EVT lines and isolated primary EVTs. The expressions of CD44 and MMP9 were also upregulated by WNT ligands. WNT10B knockdown significantly inhibited EVT invasion concomitantly with CD44 expression. The WNT canonical pathway activator upregulated CD44 expression and its inhibitor downregulated it with WNT10B addition. Conclusions: The present study is the first to show the possibility that WNT3A, WNT5A, and WNT10B exist upstream of CD44 in EVTs. Among them, WNT10B may be a novel accelerator of EVT invasion. WNT signaling mediated by multiple WNT ligands may contribute to EVT invasion.