IFPA Award in Placentology Lecture: Biology of the placental syncytiotrophoblast – Myths and facts

doi:10.1016/j.placenta.2009.12.001

Placenta

Volume 31, Supplement, March 2010, Pages S75-S81

https://doi.org/10.1016/j.placenta.2009.12.001 Get rights and content

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, aponecrotic and necrotic are discussed as being responsible for the maternal inflammatory response during pre-eclampsia.

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 syncytiotrophoblast 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.

Section snippets

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 syncytiotrophoblast. 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

Morphology of villous trophoblast nuclei

The cells residing in the layer of the cytotrophoblast display various stages of differentiation from undifferentiated and proliferative cells to highly differentiated cells just prior to fusion with the syncytiotrophoblast. All nuclei within the latter have left the cell cycle and thus the syncytiotrophoblast is terminally differentiated and no longer capable of undergoing mitosis.

Cytotrophoblasts change their appearance from proliferation to high differentiation, which can be traced by

Nuclear morphology and its relation to transcriptional activity

Gene expression during cellular differentiation is regulated by the availability of regulatory proteins and the accessibility of the DNA to the transcriptional apparatus. Position-effect variegation may place euchromatic genes adjacent to regions of heterochromatin and thus result in inactivation of euchromatic genes by heterochromatin spreading [12]. Hence, increased heterochromatization as found in nuclei of the syncytiotrophoblast could well lead to rearrangement of euchromatic chromosomal

General mechanisms to stabilize and store RNA

In the world of insects and their larval development much is known about ways to stabilize and store RNA [22]. In Drosophila most of the embryonic mRNA species have half-lives between 2 h and 30 h [23]. By 41 h of larval development 90% of the nonhistone mRNA species have decayed, telling us that 10% of all mRNA species remain in the cells for more than 40 h. Proteins derived from the stable mRNA population remain for up to 91 h and mostly comprise structural proteins such as actin, tubulin and

Transcription of RNA and translation of proteins within the syncytiotrophoblast

There is general agreement that the transcriptional activity of nuclei within the syncytiotrophoblast is downregulated and that only a proportion of nuclei within the syncytiotrophoblast are still actively engaged in producing RNA transcripts [2], [8], [10]. Ellery et al. [10] showed that only a few syncytial nuclei are stained with an antibody against the phosphoserine 2 version of RNA polymerase II. Furthermore, these authors proved that only a small subset of syncytial nuclei stained for

Protrusions of the villous surface: syncytial sprouts and knots or flat sections?

Mushroom-shaped protrusions of the syncytiotrophoblast containing multiple nuclei have been described as signs of sprouting of villi, i.e. syncytial sprouts [36] or as signs of nuclear ageing and shedding, i.e. syncytial knots [11], [37].

However, most of the seemingly protruding multinucleated structures that have been reported in literature from the analysis of two dimensional paraffin sections do not represent the three-dimensional characteristics of sprouts and knots. Rather, they mostly

Sites of villous growth: syncytial sprouts

True syncytial sprouts serve as initial structures that protrude from the villous surface during villous sprouting and thus represent syncytial structures needed for further growth of the villous tree [36]. Syncytial sprouts contain large ovoid nuclei with a prominent nucleolus and only little heterochromatin. The nuclei are loosely arranged and do not show any signs of apoptosis. Moreover, syncytial sprouts are characterized by large amounts of free ribosomes and rough endoplasmic reticulum, a

Sites of release of apoptotic material: syncytial knots

True syncytial knots are characterized by a bulbous or even mushroom-like appearance with densely packed nuclei and very few organelles and free ribosomes. More than 25 years ago they were identified as a mechanism to extrude aged syncytial nuclei [11]. It is generally accepted that the following mechanisms occur during the release of old nuclei. (1) Accumulation of aged nuclei, (2) generation of the protrusions, i.e. syncytial knots, (3) pinching off of the knots into the maternal circulation,

Trophoblast release in normal and pathological cases

Syncytial fragments containing varying numbers of nuclei have been described to be present during normal pregnancy in blood of uterine veins behind the placenta and in maternal blood between placenta and lungs [37]. Their increase in cases suffering from pre-eclampsia [38] fits with the increased rates of syncytiotrophoblast apoptosis noted in such cases [42] and the increased budding of the syncytiotrophoblast as already reported by Tenney and Parker [43]. The nuclei within syncytial fragments

Conclusions

There is no doubt that the placental syncytiotrophoblast undergoes a constant renewal throughout pregnancy. Cytotrophoblasts are continually incorporated into the syncytiotrophoblast by means of initiator caspases, proteases known to be involved in apoptosis as well. As a result, nuclei of varying transcriptional activity and heterochromaticity can be detected in this multinucleated layer. The fate of a nucleus in the layer of the villous trophoblast is similar to the fate of a cell in a

Conflict of interest

The author discloses no financial and personal relationship with other people or organizations that could have inappropriately influenced this work.

Acknowledgements

The author wants to thank Ernst Bock for his excellent help in preparing the schematic drawings in Fig. 1. This work was supported by a research grant of the European Union (Grant # 037244, project title Pregenesys).

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IFPA Award in Placentology Lecture: Biology of the placental syncytiotrophoblast – Myths and facts

Abstract

Introduction

Section snippets

Syncytial growth and Caenorhabditis elegans

Morphology of villous trophoblast nuclei

Nuclear morphology and its relation to transcriptional activity

General mechanisms to stabilize and store RNA

Transcription of RNA and translation of proteins within the syncytiotrophoblast

Protrusions of the villous surface: syncytial sprouts and knots or flat sections?

Sites of villous growth: syncytial sprouts

Sites of release of apoptotic material: syncytial knots

Trophoblast release in normal and pathological cases

Conclusions

Conflict of interest

Acknowledgements

Taiwan J Obstet Gynecol

Placenta

Placenta

Placenta

Placenta

J Ultrastruct Res

Adv Genet

Biochem Biophys Res Commun

Dev Biol

Dev Biol

J Biol Chem

J Mol Cell Cardiol

J Biol Chem

FEBS Lett

Biochim Biophys Acta

Exp Cell Res

Placenta

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Placenta

Placenta

Placenta

Am J Obstet Gynecol

Am J Pathol

Am J Obstet Gynecol

Placenta