MicroRNA-218-5p Promotes Endovascular Trophoblast Differentiation and Spiral Artery Remodeling
MicroRNA-218-5p Promotes Endovascular Trophoblast Differentiation and Spiral Artery Remodeling
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DOI：
10.1016/j.ymthe.2018.07.009
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发表时间：
2018-09-05
影响因子：
12.4
通讯作者：
Peng, Chun
中科院分区：
文献类型：
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作者：
Brkic, Jelena;Dunk, Caroline;Peng, Chun
先兆子痫（PE）是孕产妇和新生儿发病率和死亡率的主要原因。滋养细胞侵袭缺陷、血管内绒毛外滋养细胞（enEVTS）分化和螺旋动脉重塑是PE发生的关键因素。临床上没有可用于预测PE的标志物，因此加速分娩是唯一有效的治疗方法。miRNA在临床组织和母体循环中的失调为生物标志物的发现开辟了新的途径。在这项研究中，我们研究了miR-218- 5 p在PE发展中的作用。miR-218- 5 p在EVT中高表达，在PE胎盘中显著下调。使用早期妊娠滋养层细胞系和人胎盘外植体，我们发现miR-218- 5 p过表达促进而抗miR-218 - 5 p抑制滋养层侵袭、EVT生长和enEVT分化。此外，miR-218- 5 p在蜕膜-胎盘共培养中加速螺旋动脉重塑。miR-218- 5 p的作用是通过抑制转化生长因子（TGF）-β 2信号传导介导的。TGF β 2的沉默模拟了miR-218 - 5 p的作用，而TGF β 2的治疗部分逆转了miR-218- 5 p的作用。综上所述，这些发现表明miR-218- 5 p通过新的miR 218 - 5 p-TGF-β 2途径促进滋养层侵袭和enEVT分化。这项研究阐明了miRNA在enEVT分化和螺旋动脉重塑中的作用，并表明miR-218- 5 p的下调有助于PE的发展。
Preeclampsia (PE) is the leading cause of maternal and neonatal morbidity and mortality. Defects in trophoblast invasion, differentiation of endovascular extravillous trophoblasts (enEVTs), and spiral artery remodeling are key factors in PE development. There are no markers clinically available to predict PE, leaving expedited delivery as the only effective therapy. Dysregulation of miRNA in clinical tissues and maternal circulation have opened a new avenue for biomarker discovery. In this study, we investigated the role of miR-218-5p in PE development. miR-218-5p was highly expressed in EVTs and significantly downregulated in PE placentas. Using first-trimester trophoblast cell lines and human placental explants, we found that miR-218-5p overexpression promoted, whereas anti-miR218- 5p suppressed, trophoblast invasion, EVT outgrowth, and enEVT differentiation. Furthermore, miR-218-5p accelerated spiral artery remodeling in a decidua-placenta co-culture. The effect of miR-218-5p was mediated by the suppression of transforming growth factor (TGF)-beta 2 signaling. Silencing of TGFB2 mimicked, whereas treatment with TGF-b2 partially reversed, the effects of miR-218-5p. Taken together, these findings demonstrate that miR-218-5p promotes trophoblast invasion and enEVT differentiation through a novel miR218- 5p-TGF-beta 2 pathway. This study elucidates the role of an miRNA in enEVT differentiation and spiral artery remodeling and suggests that downregulation of miR-218-5p contributes to PE development.