Direct Involvement of HERV-W Env Glycoprotein in Human Trophoblast Cell Fusion and Differentiation

Abstract

We recently demonstrated that the product of the HERV-W env gene, a retroviral envelope protein also dubbed syncytin, is a highly fusogenic membrane glycoprotein inducing the formation of syncytia on interaction with the type D mammalian retrovirus receptor. In addition, the detection of HERV-W Env protein (Env-W) expression in placental tissue sections led us to propose a role for this fusogenic glycoprotein in placenta formation. To evaluate this hypothesis, we analyzed the involvement of Env-W in the differentiation of primary cultures of human villous cytotrophoblasts that spontaneously differentiate by cell fusion into syncytiotrophoblasts in vitro. First, we observed that HERV-W env mRNA and glycoprotein expression are colinear with primary cytotrophoblast differentiation and with expression of human chorionic gonadotropin (hCG), a marker of syncytiotrophoblast formation. Second, we observed that in vitro stimulation of trophoblast cell fusion and differentiation by cyclic AMP is also associated with a concomitant increase in HERV-W env and hCG mRNA and protein expression. Finally, by using specific antisense oligonucleotides, we demonstrated that inhibition of Env-W protein expression leads to a decrease of trophoblast fusion and differentiation, with the secretion of hCG in culture medium of antisense oligonucleotide-treated cells being decreased by fivefold. Taken together, these results strongly support a direct role for Env-W in human trophoblast cell fusion and differentiation.In humans, fetal cytotrophoblasts play a key role both in the embryo implantation process and in placental development. In early pregnancy, mononuclear cytotrophoblasts proliferate and invade the maternal endometrium to form the anchoring villi (4,14). Cytotrophoblasts also fuse and differentiate into a continuous layer of multinucleated syncytiotrophoblast. This cell layer, which covers the chorionic villi, is bathed by maternal blood in the intervillous spaces from early gestation (31, 34). The syncytiotrophoblast layer plays a major role throughout pregnancy, since it is the site of numerous placental functions including ion and nutrient exchange and the synthesis of steroid and peptide hormones required for fetal growth and development (13, 33). Some of these hormones, such as human chorionic gonadotropin (hCG) and human placental lactogen, are specific to pregnancy and can be used as markers of syncytium formation (20,22).It has been established both in vivo and in vitro that the syncytiotrophoblast layer arises from the differentiation and fusion of mononuclear cytotrophoblasts. Isolated mononuclear cytotrophoblasts aggregate and fuse to form a nonproliferative multinucleated syncytiotrophoblast which synthesizes and secretes specific hormones required for fetal development (2,25). This cytotrophoblast differentiation is stimulated in vitro by a number of factors such as growth factors (epidermal growth factor, granulocyte-macrophage colony-stimulating factor) and hormones (hCG, estradiol, and dexamethasone). We recently ...

Osteoclast Fusion: Time‐Lapse Reveals Involvement of CD47 and Syncytin‐1 at Different Stages of Nuclearity

“…There are only very few studies that have addressed the involvement of syncytin‐1 in cell fusion and at the same time stratified for the number of nuclei in the resulting cells. However, Frendo and colleagues (Frendo et al, 2003) did so when investigating the fusion of primary human cytotrophoblasts in the presence or absence of syncytin‐1 anti‐sense RNA. They found, using end‐point analyses, that only the frequency of syncytia with six nuclei or more was significantly reduced, which supports data from our present study.…”

Development and hormonal functions of the human placenta.

“…glycoprotein of HERVW retrovirus is directly involved in trophoblast fusion and differentiation [3]. In the extravillous phenotype, the cytotrophoblastic cells of the anchoring villi in contact with the uterine wall proliferate, detach from the basement membrane and aggregate into multilayered columns of nonpolarised cells that rapidly invade the uterus wall.…”

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

“…Among the HERVs, the MS retrovirus, HERV-H, and the HERV-W envencoded glycoprotein, Syncytin-1, have been reported to participate in MS neuropathogenesis (22)(23)(24)(25)(26). Syncytin-1, encoded by the HERV-W env gene, ERVWE1, on chromosome 7q21.2 is expressed in the placenta, and its role in health is likely to mediate syncytial fusion of the villous trophoblast (27). Previous studies also indicate that Syncytin-1 also contributes to neuroinflammation and oligodendrocyte death (23,28).…”