IFPA Award in Placentology Lecture: Biology of the placental syncytiotrophoblast – Myths and facts B. Huppertz * Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria article info Article history: Accepted 2 December 2009 Keywords: Placenta Villous trophoblast Syncytiotrophoblast Morphology Pre-eclampsia abstract About 15 years ago apoptosis was attributed a role in the development of the human placenta. Since then an increasing number of publications has shown that programmed cell death plays an essential role in placental growth and differentiation, especially in the villous trophoblast. During the last ten years a concept was established linking the progress of apoptosis to differentiation of cytotrophoblasts and syncytiotrophoblast. Thus, development and maintenance of the syncytiotrophoblast depends on the precise orchestration of different processes and stages of the apoptosis cascade. This review focuses on the maintenance and growth of the syncytiotrophoblast as well as the deportation of trophoblast material into the maternal circulation. Nuclear morphology is related to transcriptional activity, RNA protection and storage strategies are discussed and the differences between syncytial expression rates of RNA and protein are highlighted. Moreover, deportation of trophoblast fragments is related to the relevant morphological structures (syncytial knots) and to their effects on the maternal system. Finally, different modes of release of trophoblast fragments such as apoptotic, apo- necrotic and necrotic are discussed as being responsible for the maternal inflammatory response during pre-eclampsia. Ó 2010 Published by IFPA and Elsevier Ltd. 1. Introduction The villous trees of the human placenta are covered by a singular epithelial tissue, the villous trophoblast. This tissue is unique in that it is composed of a layer of mononucleated villous cytotrophoblasts covered by a layer generated and maintained by syncytial fusion. This villous syncytiotrophoblast does not contain lateral cell borders and thus is a typical syncytium with a multinucleated appearance and membranes only on the apical and basal side. It covers all villous trees of a placenta and hence there is a single syncytiotrophoblast in each placenta [1]. As the outermost layer covering the chorionic villi, the syncy- tiotrophoblast is the only villous tissue in a placenta that comes into direct contact with maternal blood throughout pregnancy. In this localization the syncytiotrophoblast is essential for the embryo and fetus in terms of immunological defense mechanisms, active transport and expression of proteins, hormones, cytokines and chemokines. Recently a new hypothesis has been formulated in an attempt to shed some new light on the maintenance and turnover of the syncytiotrophoblast [2]. New ideas and hypotheses are crucial for the development of science. At the same time such hypotheses need to have a solid base and relevant experimental data to support the new idea. Thus, there seems to be a need to clarify the way the syncytiotrophoblast is maintained and how apoptotic material is deported by syncytial knots. 2. Syncytial growth and Caenorhabditis elegans Volume growth of the syncytiotrophoblast may be achieved not only by incorporation of cytotrophoblasts; rather syncytial volume might further be gained by internal growth of the syncytio- trophoblast. Similar mechanisms have been discussed in volume gain of the hyp7 syncytium of Caenorhabditis elegans (C. elegans) [3]. This study found that fusing seam cells (the precursor cells of the hyp7 syncytium) contributed less than 10% to the total volume increase of hyp7. Knight et al. [3] speculated that the main function of seam cell proliferation and fusion may be to supply the hyp7 syncytium with additional genomes for the purpose of growth. Growth of the syncytiotrophoblast in terms of increasing the number of nuclei is provided by continuous fusion of cytotropho- blasts with the syncytiotrophoblast throughout gestation. In the first half of pregnancy, the cytotrophoblast layer is a complete layer of cuboidal mononucleated cells. During the course of pregnancy, cytotrophoblasts change their cellular shape. In the second half of * Tel.: þ43 316 380 7604; fax: þ43 316 380 9625. E-mail address: berthold.huppertz@medunigraz.at Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta 0143-4004/$ – see front matter Ó 2010 Published by IFPA and Elsevier Ltd. doi:10.1016/j.placenta.2009.12.001 Placenta 31, Supplement A, Trophoblast Research, Vol. 24 (2010) S75–S81