The BMP2 Signaling Axis Promotes Invasive Differentiation of Human Trophoblasts.

Jiali You,Guofang Feng,Yi-Min Zhu,Yuyin Yi,Peter C K Leung,Shaobing Cheng,Hua Zhu,Yu Sun,Hongjin Zhao,Minyue Tang,Yimiao Sang,Chunyan Wang,Wei Wang,Hsun-Ming Chang

doi:10.3389/fcell.2021.607332

Abstract

Embryo implantation and trophoblast invasion are principal limiting factors of pregnancy establishment. Aberrant embryo development or improper trophoblast differentiation and invasion may lead to various unfavorable pregnancy-related outcomes, including early pregnancy loss (EPL). Our clinical data show that the serum BMP2 levels were significantly increased during the first trimester of pregnancy and that the serum and BMP2 expression levels were lower in women with EPL than in women with normal early pregnancies. Moreover, we observed that BMP2 was expressed in oocytes and trophoblast cells of cleaved embryos and blastocysts prior to implantation in both humans and mice. Exogenous BMP2 promoted embryonic development by enhancing blastocyst formation and hatching in mice. LncRNA NR026833.1 was upregulated by BMP2 and promoted SNAIL expression by competitively binding to miR-502-5p. SNAIL induced MMP2 expression and promoted cell invasion in primary extravillous trophoblast cells. BMP2 promotes the invasive differentiation of mouse trophoblast stem cells by downregulating the expression of TS cell marker and upregulating the expression of trophoblast giant cell marker and labyrinthine/spongiotrophoblast marker. Our findings provide significant insights into the regulatory roles of BMP2 in the development of the placenta, which may give us a framework to explore new therapeutic strategies to pregnancy-related complications.

Highlights

Implantation of a competent blastocyst into a receptive uterus is key for the establishment of pregnancy
BMP2 did not have such effects on the expression of MMP9 and other Matrix metalloproteases (MMPs) (Supplementary Figure 4). These results indicate that BMP2 promotes cell invasion, most likely, by upregulating the expression of MMP2 in primary Extravillous trophoblasts (EVTs) cells
SNAIL knockdown completely abolished BMP2-induced increases in cell invasion (Figure 3C and Supplementary Figure 5). These results indicate that SNAIL is the main transcription factor that mediates the BMP2-induced trophoblast cell invasion

Summary

Introduction

Implantation of a competent blastocyst into a receptive uterus is key for the establishment of pregnancy. Extravillous trophoblasts (EVTs) are derived from cytotrophoblast cells in the anchoring columns under the influence of growth factors and cytokines derived from many cells, including decidual macrophages, uterine NK cells and stromal cells. After migration from the attached embryo, these highly invasive EVTs appropriately invade the uterine epithelium and uterine spiral arteries, a process that is indispensable for proper placentation and successful establishment of mammalian pregnancy (Wehrum et al, 2011; Gupta et al, 2016). The occurrence of EVT invasion in the endometrial stroma and myometrium (inner third) is critical for developing definitive maternalfetal circulation and successful pregnancy (Cakmak and Taylor, 2011). Aberrant trophoblast (EVT or syncytiotrophoblast) differentiation or improper trophoblast invasion may lead to various unfavorable pregnancy-related outcomes, including early pregnancy loss (EPL), preeclampsia, intrauterine growth restriction, and choriocarcinoma (Brosens et al, 2011)

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