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Berthold Huppertz, PhD:

Interplay between placental trophoblast turnover / release and maternal endothelium response

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Chair of Cell Biology, Histology and Embryology, Medical University of Graz, 8010 Graz, Neue Stiftingtalstraße 6(MC1.C.)/II; phone: +43-316-385 71897, fax: +43-316-380 72731, ✉ e-mail

Keywords:

Placenta, preeclampsia, fetal growth restriction, trophoblast, syncytial fragments, apoptosis, aponecrosis, maternal serum, predictive biomarkers, turnover

Research interest:

Aponecrotic release of subcellular fragments from the placental trophoblast is one of the main features of preeclampsia, while failure in trophoblast invasion is one of the main features of fetal growth restriction (FGR). Pregnancy per se is an immunological challenge for the mother, and non-self cells and cellular debris needs to be dealt with throughout pregnancy. The etiologies of preeclampsia and FGR have been refined a couple of years ago while respective new developments in research on the topic are still missing (1). The main focus of our laboratory is to identify the pathways and mechanisms leading to the onset of the placental defects in preeclampsia and FGR and how they interfere with the maternal immunological defense system (2, 3). In preeclampsia specific placental proteins such as placental protein 13 (PP13) released from the trophoblast have been identified as putative predictive markers of preeclampsia (4). At the same time, other factors, mostly angiogenic factors such as sFlt-1 and PlGF, have been reported and are now in use as markers for bad pregnancy outcome (including preeclampsia and FGR). The origin of the latter factors is not clear yet and both individuals, mother and fetus, are discussed as sources (5, 6). In FGR trophoblast invasion seems to be impaired. Until recently, trophoblast invasion was supposed to take place at only two different sites, the interstitium of the decidua / inner third of the myometrium of the placental bed to anchor the placenta to the uterus, and from the interstitium towards the lumen of spiral arteries thereby transforming such vessels to open conduits without vasomotor control of the mother. Quite recently, new pathways of trophoblast invasion have been described urging to revisit what has been known about trophoblast invasion. It now has become clear that invasive trophoblasts also reach uterine glands, open these structures towards the intervillous space of the placenta and hence enable histiotrophic nutrition of the embryo during the first trimester of pregnancy (7, 8). Very recent data suggest that also uterine veins are invaded and thus opened towards the intervillous space. It needs to be elucidated what are the effects of a failure of invasion towards such structures.

Illustrations:

Fig. 1: The villous trophoblast in pre-eclampsia.

References:

  1. Sreckovic I, Birner-Gruenberger R, Obrist B, Stojakovic T, Scharnagl H, Holzer M, Scholler M, Philipose S, Marsche G, Lang U, Desoye G, Wadsack C: Distinct composition of human fetal HDL attenuates its anti-oxidative capacity. Biochim Biophys Acta, 2013; 1831(4):​737–746.
  2. Sreckovic I, Birner-Gruenberger R, Besenboeck C, Miljkovic M, Stojakovic T, Scharnagl H, Marsche G, Lang U, Kotur-Stevuljevic J, Jelic-Ivanovic Z, Desoye G, Wadsack C: Gestational diabetes mellitus modulates neonatal high-density lipoprotein composition and its functional heterogeneity. Biochim Biophys Acta, 2014; 1841(11):​1619–1627.
  3. Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Fogelman AM: HDL as a biomarker, potential therapeutic target, and therapy. Diabetes, 2009; 58(12):​2711–2717.
  4. Lambertini M, Peccatori FA, Azim HA Jr: Targeted agents for cancer treatment during pregnancy. Cancer Treat Rev, 2015; 41(4):​301–309.   

Collaborations within the DP-iDP:

               
  • G. Desoye will introduce the isolation of trophoblast cells from first-trimester and term placenta.
  • C. Wadsack will provide insight into ex vivo placental perfusion of term placentas and help students to collect subcellular material derived from the trophoblast.
  • M. Gauster will help in culturing trophoblast and endothelial cells and perform further Analysis.

Collaborating research groups where PhD students could perform their research stay abroad:

  • I. Cetin (University of Milan, Italy) is an obstetrician with a very long lasting experience in fetal growth restriction. She will introduce the students on how to recruit patients and collect samples with respective clinical data.
  • U. Markert (University of Jena, Germany) is the head of the placenta lab in Jena and will teach the students how to perform analysis of miRNA from trophoblast fragments.
  • P.  Brownbill (University of Manchester, UK) will provide insight into ex vivo placental perfusion using differential flow velocities during perfusion.

Industrial partners:

HyLabs, Israel; KiWi, Austria.

Know-how and infrastructure of the research group:       

The laboratory of Berthold Huppertz has a very long-standing expertise in the field of placental cell biology and morphology, as well as in pregnancy pathologies, especially preeclampsia and fetal growth restriction. Studies are carried out with isolated primary cells from the human placenta (first-trimester and term) as well as using trophoblast-derived cell lines for transfection / silencing experiments. Various methodologies and techniques are used for a detailed cell-biological analysis of trophoblast and endothelial cell function. All the required equipment is available at the institute, including cell culture facilities, a hypoxic works chamber with four units (each adjustable on its own pO2), time-lapse microscopy, real-time PCR systems, fluorescence plate reader, fluorescence western blot analysis, tissue processing and fluorescence microscopy, laser scanning microscopy and a microscopy system for stereological assessment of slides. Since Berthold Huppertz is also head of the Organisational Unit of Research Infrastructure, the group has also access to all core facilities of the Center for Medical Research.

Scientific concepts and techniques that students will learn in this laboratory:

 

DP-iDP students will be trained in placental biology and will receive insights in the turnover of placental trophoblast and its effect on endothelial cell function. In addition, they will get background knowledge on current concepts of the etiologies of preeclampsia and fetal growth restriction and where demand for future research exists. The acquired methodologies will comprise isolation and culturing of cells from placenta as well as culturing placental explants, RNA techniques including siRNA gene knock-down, western blot, immunohistochemistry and fluorescent staining, time-lapse microscopy and laser-scanning microscopy.

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