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

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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.

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Acknowledgments

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.

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  1. Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, Universitaetsstr. 21-23, 91054, Erlangen, Germany

    Matthias Ruebner, Pamela L. Strissel, Manuela Langbein, Florian Faschingbauer, Matthias W. Beckmann & Reiner Strick

  2. Department of Paediatrics and Adolescent Medicine, University-Clinic Erlangen, 91054, Erlangen, Germany

    Fabian Fahlbusch

  3. Institute for Pathology, University-Clinic Erlangen, 91054, Erlangen, Germany

    David L. Wachter

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  1. Matthias Ruebner
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Ruebner, M., Strissel, P.L., Langbein, M. et al. Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes. J Mol Med 88, 1143–1156 (2010). https://doi.org/10.1007/s00109-010-0656-8

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