Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes

Abstract

One leading cause of perinatal morbidity and mortality is intrauterine growth restriction (IUGR). Several causes for IUGR have been proposed involving cytotrophoblast dysfunction. Envelope genes of the human endogenous retrovirus (HERV)-W (Syncytin-1), -FRD (Syncytin-2), and -P(b) have fusogenic properties, whereas envelope genes of HERV-R, -V1, and -V2 have putative placental functions. All six HERV envelope genes and three known cellular receptors were analyzed for expression in human control and IUGR placentae (n = 38) and in cultured cytotrophoblasts from control and IUGR (n = 8) placentae. All envelope genes demonstrated downregulation in IUGR compared to control placentae tissues, which were confirmed with cultured cytotrophoblasts. Examination of the Syncytin-1 and Syncytin-2 receptors ASCT-1/-2 and MFSD2 showed that MFSD2 was significantly expressed lower in IUGR than in control placentae and cytotrophoblasts. A reduction of Syncytin-1 protein expression was confirmed for IUGR placentae with immunoblotting and paraffin tissue sections. Embedded placental IUGR tissues showed an overall disorganized syncytiotrophoblast layer with fewer nuclei. Cytotrophoblasts from IUGR placentae demonstrated a lower cell fusion index and nuclei per syncytiotrophoblast in vitro. Fusogenic and non-fusogenic envelope genes are dysregulated in IUGR placentae and may contribute to the etiology of growth restriction in utero.

A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin

“…Interestingly, placental intrauterine growth restriction is correlated with significantly decreased MFSD2A and glucose levels, raising the possibility that reduced MFSD2A function might lead to diminished accumulation of an unidentified growth-promoting substrate (71). Findings in mice that show MFSD2A up-regulation in liver and brown adipose tissue (BAT) upon fasting and cold-induced thermogenesis in BAT offer the possibility for a potential role of MFSD2A in uptake of an unknown molecule (34,72).…”

Syncytins expression in cultured trophoblast cells according to differentiation status

“…Beta chorionic gonadotropin (β-hCG) production is widely used as a marker of differentiation in trophoblast cells cultures and is thought to correlate positively with the differentiated syncytiotrophoblast presence [4,[25][26][27]. Syncytiotrophoblast is considered to be the main site of β-hCG production and higher levels of this molecule are compatible with increased levels of syncytia in the cell population [4].…”

“…Finally, studies of the relative expression of the syncytins in abnormal placentation and myometrial invasion conditions and comparison to the normal expression pattern of these biomolecules could provide with useful information regarding the pathophysiology of placental dysfunction. Evidence of lower syncytins expression exist in preeclampsia [30,31], HELLP [32] or IUGR [27] with no apparent effect on ASCT2 expression [33] but no studies have been conducted upon syncytin 2 receptor.…”

Mechanism of Congenital Chagas Disease: Effective Infection Depends on the Interplay Between Trypanosoma cruzi and the Different Tissue Compartments in the Chorionic Villi of the Human Placenta

“…Some of these factors, considered as trophoblast "differentiation markers" or "fusion markers", are the following: a. Syncytin family proteins: Syncytins are fusogenic proteins encoded by envelope genes (env genes) of the human endogenous retrovirus (HERV)-W (Syncytin-1), (HERV)-FRD (Syncytin-2), and (HERV)-P(b) (Syncytin-3;) (Ruebner et al, 2010). HERVs contribute to genome plasticity, protect the host against infection with related pathogenic and exogenous retroviruses, and play a vital role in the development of the placenta (Black et al, 2010).…”