Review: Does size matter? Placental debris and the pathophysiology of pre-eclampsia
Introduction
Over 100 years ago, Schmorl, a German pathologist, described multinucleate cells in the pulmonary capillaries of 17 women who died of eclampsia (cited in Ref. [1]). Although at first it was thought that these were specific lesions of eclampsia, his work and that of others then showed they also occurred in pre-eclampsia. This was subsequently named trophoblast deportation. Much later it was realised that this is just one aspect of a much broader process of shedding cellular and sub-cellular structures from the syncytial epithelium of the human placenta (Fig. 1). These have been loosely called debris [2]. The term may not be appropriate since some of the structures described here seem to have signalling functions. They vary in size, over about four orders of magnitude from deported fragments to exteriorised intracytoplasmic molecules (Table 1).
A comprehensive survey of autopsies of pregnant women, who died for various reasons [1], showed deported trophoblast in lungs of women as early as the first and second trimesters, with ectopic pregnancies, in relation to sepsis or haemorrhage and shock, and persisting for up to 2 weeks after delivery. The authors speculated that deportation occurred in all pregnancies, but found the highest incidence in those complicated by pre-eclampsia and eclampsia.
Deported multinucleate trophoblasts are retained in the pulmonary circulation and rarely detected in peripheral vein blood. We studied plasma from uterine vein blood taken at caesarean section before labour and confirmed earlier evidence that significantly more trophoblast is deported in pre-eclampsia than in normal control samples [3]. We described a variety of deported forms: mononuclear and different types of multinuclear structures that could be derived from syncytial sprouts or knots. The subject has just been extensively reviewed [4], [5].
These were first prepared as an in vitro artefact from term placentas in order to isolate syncytiotrophoblast membrane for studies of its biochemistry and functions, especially transport functions [6]. Later we discovered, using a syncytiotrophoblast specific ELISA, that similar microvesicles (MVs) circulate in the plasma of normal pregnant women, in increasing amounts from late in the first trimester onwards and in significantly increased amounts in pre-eclampsia [7], [8]. At this time it was increasingly evident that MVs of diverse cellular origins normally circulate in non-pregnant and pregnant individuals alike, the most abundant derived from platelets (reviewed in [9]). Several specific functions for platelet MVs have been defined (reviewed in [10]). It is now considered that probably all eukaryotic cells generate MVs after activation or apoptosis and that they are a universal means of inter-cellular communication [11].
Section snippets
Production of syncytiotrophoblast microvesicles
In vivo the term MVs sometimes includes apoptotic bodies and apoptotic-MVs, as well as activation induced-MVs. The last two are produced by blebbing of the plasmalemma but in response to different stimuli and mechanisms [12]. Apoptotic bodies may contain cell organelles and be up to 3 μm in diameter. Apoptotic-MVs are smaller and are stimulated by different apoptotic pathways [12].
For experimentation, there are several sources of STBM (Table 2) and evidence that they are not equivalent. A major
Microvesicles, maternal systemic inflammation and immunomodulation
That mSTBM are inhibitory and pSTBM are pro-inflammatory may be because these populations contain different types of MVs, some of which may be non-physiological and therefore irrelevant to in vivo processes. But involvement with inflammatory responses may be a key to understanding the pathogenesis of pre-eclampsia.
Normal pregnancy evokes a maternal systemic inflammatory response, especially towards the end of the third trimester [17]. This manifests in several ways, summarized previously [18],
Danger molecules and the inflammatory response
It has long been known that the innate immune response is “hard wired” and rapid in contrast to the adaptive immune response. Originally an innate immune response was thought to occur only to external dangers, notably infection, but a more extended role has been recognised recently; that it is activated by ‘‘danger’’ signals interacting with a range of ‘‘pattern recognition receptors’’ that have evolved to respond in a wide but essentially stereotyped way [20]. The danger signal may be external
Exosomes and smaller debris
Overall, circulating STBMs are promising candidates as contributors to the systemic inflammatory responses of both normal and pre-eclamptic pregnancies. When we consider smaller MVs, we enter the relatively uncharted territory of nanovesicles or exosomes.
Enzyme linked immunoassay (ELISA)
As discussed above, the first detection of STBM in maternal plasma was carried out using an in house ELISA [7]. Cellular vesicles were isolated from diluted plasma by ultracentrifugation at 100,000 g for 1 h. The pellets were resuspended in a small volume and STBM were bound to an ELISA plate using a monoclonal antibody to placental alkaline phosphatase (NDOG2) as the capture antibody. The ELISA technique is widely used to study microvesicles and exosomes in other fields, often employing
Conclusion - does size matter?
We propose that the different functional effects of STBM (Fig. 2) result from different types of vesicles within the preparations: syncytiotrophoblast exosomes and microvesicles. Microvesicles and exosomes have different biological functions, cargos and modes of production. Exosomes are immunosuppressive amongst other properties and microvesicles may include apoptotic or necrotic material, the former immunosuppressive and the latter immunostimulatory, anti-angiogenic and procoagulant. Changes
Conflict of interest
The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.
Acknowledgements
This work was supported by a Wellcome Trust Technology Development Grant (ref GR087730), Wellcome Trust Programme Grant (ref GR079862MA) and by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The authors would like to thank Dr Carolyn Jones, University of Manchester
References (36)
- et al.
Placental debris, oxidative stress and pre-eclampsia
Placenta
(2000) - et al.
Trophoblast deportation in human pregnancy - its relevance for pre-eclampsia
Placenta
(1999) - et al.
Trophoblast deportation part I: review of the evidence demonstrating trophoblast shedding and deportation during human pregnancy
Placenta
(2011) - et al.
Trophoblast deportation part II: a review of the maternal consequences of trophoblast deportation
Placenta
(2011) - et al.
Immunology of normal pregnancy and preeclampsia
Platelet-derived microparticles - an updated perspective
Thromb Res
(2011)- et al.
Formation of procoagulant microparticles and properties
Thromb Res
(2010) - et al.
Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers
Transf Med Rev
(2006) - et al.
A comparative study of the effect of three different syncytiotrophoblast micro-particles preparations on endothelial cells
Placenta
(2005) - et al.
Preeclampsia: an excessive maternal inflammatory response to pregnancy
Am J Obstet Gynecol
(1999)