Impaired cytotrophoblast cell–cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction

Abstract

Preeclampsia (PE), Hemolysis Elevated Liver Enzymes and Low Platelets (HELLP)-syndrome, and intrauterine growth restriction (IUGR) are associated with abnormal placentation. In early pregnancy, placental cytotrophoblasts fuse and form multinuclear syncytiotrophoblasts. The envelope gene of the human endogenous retrovirus-W, Syncytin, is a key factor for mediating cell-cell fusion of cytotrophoblasts. This study investigated clinical parameters of PE and HELLP-associated IUGR and analyzed the cell-cell fusion index and beta-human chorionic gonadotropin (beta-hCG) secretion of cytotrophoblasts isolated and cultured from placentas of these patients. In addition, we performed absolute quantitation of Syncytin and determined the apoptosis rate in both cultured cytotrophoblasts and placental tissues. Cultured cytotrophoblasts from PE and HELLP-associated IUGR correlated with a pronounced lower cell-cell fusion index, 1.8- and 3.6-fold; less nuclei per syncytiotrophoblast, 1.4- and 2.0-fold; a significantly decreased beta-hCG secretion, 4.3- and 17.2-fold and a reduction of Syncytin gene expression, 8.1 (P = 0.019) and 222.7-fold (P = 0.011) compared with controls, respectively. In contrast, a significantly 2.3-fold higher apoptosis rate was observed in cultured PE/IUGR cytotrophoblasts (P = 0.043). Importantly, Syncytin gene expression in primary placental tissues of PE/IUGR was 5.4-fold lower (P = 0.047) and in HELLP/IUGR 10.6-fold lower (P = 0.019) along with a 1.8- and 1.9-fold significant increase in the apoptosis rate compared with controls, respectively. Low Syncytin expression in both cultured cytotrophoblasts and primary tissues from pathological placentas supports an intrinsic placenta-specific deregulation of cell-cell fusion in the formation of syncytiotrophoblasts leading to increased apoptosis. These processes could contribute to the development and severity of PE and HELLP-associated IUGR.

Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line

“…Disturbed trophoblast fusion and syncytiotrophoblast formation has been linked to the pathogenesis of pregnancy-related complications such as pre-eclampsia, intrauterine growth restriction (IUGR), and haemolysis elevated liver enzymes and low platelets (HELLP)-syndrome (Gauster et al, 2009;Langbein et al, 2008) A number of proteins have been identified as crucial regulators of trophoblast cell fusion. Syncytin-1, a protein encoded by a human endogenous retrovirus-W envelope protein gene (Mi et al, 2000), is abundantly expressed in placental trophoblasts and appears to be critical for trophoblast fusion.…”

Effects of Reduced Gcm1 Expression on Trophoblast Morphology, Fetoplacental Vascularity, and Pregnancy Outcomes in Mice

“…In PE, growing evidence implicates abnormalities in syncytiotrophoblast (SynT) in the villous exchange region of the placenta. [1][2][3][4][5][6] SynTs are thin, fetal-derived cells that lie between the maternal blood flowing through the villous exchange region of the placenta and the fetal blood flowing through fetal vessels in the highly vascularized villi. This surface is essential for fetomaternal communication and exchange and is formed through the differentiation of SynT from the underlying villous cytotrophoblast cells under the control of the transcription factor GCM1 (glial cells missing 1).…”

Silver nanoparticles exhibit size-dependent differential toxicity and induce expression of syncytin-1 in FA-AML1 and MOLT-4 leukaemia cell lines

“…It is also know to suppress apoptosis in choriocarcinoma cells (41) and low levels of syncytin-1 have been linked to placental dysfunction in pre-eclampsia (42)(43)(44). Most significantly expression of syncytin-1 has also been shown to suppress staurosporin-induced apoptosis in Chinese hamster ovary (CHO) cells (45) Although there is significant evidence for syncytin-1 conferring a growth/survival advantage in malignant cells, there is also evidence that its expression induces demyelination and cell death in oligodendrocytes which is consistent with the protein playing a causative role in neurodegenerative disease (48).…”