Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes
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.
KeywordsPlacentogenesis Cell fusion HERV IUGR Syncytin-1 Trophoblast
The authors are especially grateful to the patients who participated in this study and to the Dept. of Gynaecology and Obstetrics, Erlangen. The authors thank Dr. Kristina Becker (Inst. for Biochemistry, University of Erlangen-Nuremberg) and Florentine Koppitz and Elisabeth Stiegler (Dept. of Gynaecology and Obstetrics, Erlangen) for expert technical assistance. This work was supported by a grant from the “Deutsche Forschungsgemeinschaft” (DFG) to RS.
- 15.Mallet F, Bouton O, Prudhomme S, Cheynet V, Oriol G, Bonnaud B, Lucotte G, Duret L, Mandrand B (2004) The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc Natl Acad Sci USA 101:1731–1736. doi: 10.1073/pnas.0305763101 0305763101CrossRefPubMedGoogle Scholar
- 23.Strick R, Ackermann S, Langbein M, Swiatek J, Schubert SW, Hashemolhosseini S, Koscheck T, Fasching PA, Schild RL, Beckmann MW, Strissel PL (2007) Proliferation and cell–cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta. J Mol Med 85:23–38. doi: 10.1007/s00109-006-0104-y CrossRefPubMedGoogle Scholar
- 26.Malassine A, Blaise S, Handschuh K, Lalucque H, Dupressoir A, Evain-Brion D, Heidmann T (2007) Expression of the fusogenic HERV-FRD Env glycoprotein (syncytin 2) in human placenta is restricted to villous cytotrophoblastic cells. Placenta 28:185–191. doi: 10.1016/j.placenta.2006.03.001 CrossRefPubMedGoogle Scholar
- 35.Langbein M, Strick R, Strissel PL, Vogt N, Parsch H, Beckmann MW, Schild RL (2008) Impaired cytotrophoblast cell–cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Mol Reprod Dev 75:175–183. doi: 10.1002/mrd.20729 CrossRefPubMedGoogle Scholar
- 38.Guilbert LJ, Winkler-Lowen B (2007) Placental alkaline phosphatase (PLAP) staining and human chorionic gonadotropin (hCG) production in cultures of fresh and cryopreserved cytotrophoblasts isolated by CD9/MHC class I/MHC class II immunoelimination. Placenta 28:348–349. doi: 10.1016/j.placenta.2006.04.011 CrossRefPubMedGoogle Scholar
- 40.Handschuh K, Guibourdenche J, Cocquebert M, Tsatsaris V, Vidaud M, Evain-Brion D, Fournier T (2009) Expression and regulation by PPARgamma of hCG alpha- and beta-subunits: comparison between villous and invasive extravillous trophoblastic cells. Placenta 30:1016–1022. doi: 10.1016/j.placenta.2009.09.006 CrossRefPubMedGoogle Scholar
- 43.Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-Fernandes S, Mandrand B, Mallet F, Cosset FL (2000) An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol 74:3321–3329CrossRefPubMedGoogle Scholar
- 65.Newhouse SM, Davidge ST, Winkler-Lowen B, Demianczuk N, Guilbert LJ (2007) In vitro differentiation of villous trophoblasts from pregnancies complicated by intrauterine growth restriction with and without pre-eclampsia. Placenta 28:999–1003. doi: 10.1016/j.placenta.2007.04.008 CrossRefPubMedGoogle Scholar