Syncytin-1 modulates placental trophoblast cell proliferation by promoting G1/S transition

Abstract

Placental syncytiotrophoblasts formed by the fusion of cytotrophoblasts constitute the interface between maternal and fetal circulations. The syncytium, composed of a continuous layer of syncytiotrophoblasts, assumes the fetal-maternal nutrient exchange, placental barrier, and endocrine functions important for the maintenance of normal pregnancy. Syncytin-1, an endogenous retroviral gene product, mediates the fusion of cytotrophoblasts. While the fusogenic function of syncytin-1 has been well established, little is known regarding its nonfusogenic activities. This study investigates the role of syncytin-1 in trophoblast proliferation. We found that syncytin-1 knockdown significantly inhibited BeWo cell growth and DNA synthesis. Moreover, time course studies on key cell cycle regulators demonstrated an upregulation of p15 and downregulation of CDK4, E2F1, PCNA, and c-Myc, which consequently led to a reduced level of CDK1. These results, together with those from flowcytometry analysis, indicated that syncytin-1 knockdown blocked the G1/S transition phase of the cell cycle. Moreover, syncytin-1 overexpression promoted CHO cell proliferation and led to changes opposite to those observed in syncytin-1 knockdown experiments, confirming the critical role of syncytin-1 for G1/S transition. Thus, syncytin-1, through both nonfusogenic and fusogenic, functions, may co-regulate the input (proliferation) and output (fusion) of the cytotrophoblast “pool”. Such co-regulation could be an efficient way to achieve the balance between these two opposing processes, which is required for syncytium homeostasis. Since decreased syncytin-1 expression has been shown to be associated with preeclamptic and hypoxic condition, insufficient replenishing of the cytotrophoblast “pool” may contribute to syncytium deficiency, a critical pathological change frequently found in preeclamptic placentas.

Morphological changes of placental syncytium and their implications for the pathogenesis of preeclampsia

“…We hypothesized that the relatively small discordance in birth weight of the studied twins may likely recapitulate the early stage of preeclamptic condition, which is characterized by mild stress in comparison to severe preeclampsia with aggravated stress. In placentas associated with the smaller fetuses, the stressed condition may upregulate syncytin-1 expression, which is able to promote the trophoblast proliferation as we have demonstrated by recent in vitro experiments through manipulation of syncytin-1 expression levels in choriocarcinoma cell cultures [16]. For the same reason, as often observed in placentas and the cardiovascular system, moderate hypoxia or ROS often leads to active angiogenesis and epithelial expansion.…”

“…These observations revealed a close relationship between syncytial structure and maternal systemic disorders. As discussed in more detail below, the reduced levels of syncytin-1, which have been shown to be a key cell-cycle regulator [16], could partially explain the decreased trophoblast proliferation in preeclamptic placentas.…”

Transport of digoxin-loaded Polymeric Nanoparticles Across BeWo cells, an In Vitro Model of Human Placental Trophoblast

“…No endotoxin contamination was expected as all studies were conducted under sterile conditions and the cell culture medium components were already tested for endotoxin contamination. A continuous trophoblast layer is important in the protective function of the placenta [26], and therefore, transepithelial e lectrical resistance (TEER) measurements were used to measure the integrity of cell monolayers [20]. TEER values were measured using an EndOhm ® voltohmmeter (World Precision Instruments, FL, USA), at 25°C starting on day 4 post seeding to ensure monolayer formation.…”

Transcriptional Derepression of the ERVWE1 Locus following Influenza A Virus Infection

“…The env gene in this locus encodes syncytin-1 (1-3), which appears to have been functionally adopted during human evolution (4,5). Syncytin-1 is highly expressed in the placenta and mediates the fusion and, possibly, proliferation of trophoblast cells (1,2,6,7). During pregnancy, syncytin-1 may also serve other purposes, such as modulating the maternal immune system (8,9).…”