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Medical University of Graz

Christian Wadsack, PhD:

Identification of bioactive lipids at the placental barrier and their functional role in inflammatory pregnancy diseases

Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, A-8036 Graz;
phone: +43-316-385 81074, fax: +43-316-385 12506, ✉ e-mail

Keywords:

human placenta, dual placental perfusion system, PlaZentaTox, materno-fetal lipid axis, (patho)physiology of the placenta, neonatal lipoproteins, bioactive lipids and enzymes, inflammatory disorders in pregnancy

Research interest:

 

The laboratory is carrying out research on the molecular mechanisms of the human placenta responsible for pregnancy diseases associated with inflammation such as gestational diabetes or pre-eclampsia. A longstanding and central interest has been on the role of lipid and lipoprotein transfer across the human placenta. Importantly, the transport of bioactive lipids and fatty acids from the mother to fetus across the placental barrier has long been neglected. We are investigating by running ex vivo placental perfusion experiments together with in vitro cell culture assays if and how bioactive lipids and lipoproteins may cross the different biological barriers of the human term placenta.

 

Another research line is focusing on the composition and functionality of neonatal high-density lipoprotein (HDL) in order to understand its role on the feto-placental endothelium and its impact on barrier function in normal and pathophysiological pregnancies (1, 2). Emerging evidence suggests that HDL function is not always accurately predicted by HDL cholesterol levels. The functions of HDL include reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of the innate immune system. In healthy individuals, in the absence of systemic oxidative stress and inflammation, HDL is anti-inflammatory. However, in those with chronic illnesses such as diabetes that are characterized by systemic oxidative stress and inflammation, HDL may actually promote the inflammatory response (i. e., it may become pro-inflammatory). HDL may be thought of as a shuttle (2).

Illustrations:

Fig. 1: Schematic of placental nanoparticle transport. In the figure the concentration of 80 nm and 500 nm polystyrene (PS) particles and 100 nm poly (lactic-co-glycolic acid) (PLGA) particles are shown during 6 h dual ex vivo placenta perfusion experiments in the maternal (M) and fetal (F) circulation. A size-depended difference in uptake and transport across the tissue can be seen between the different PS particles. The PLGA particles show a stronger placental uptake than PS particles but a reduced transport into the fetal circulation.

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. Marsche will train the PhD-students in (patho)physiology of lipoproteins and their systemic functions and in chemical as well as analytical methods to identify specific reaction products and post-translational modifications of lipoproteins.
  • M. Gauster will teach the students in physiology of first-trimester placental tissue and train to use explants of trimester placental tissue in order to study inflammatory processes in early pregnancy.
  • Á. Heinemann will train students in leukocyte leukocyte biology and pharmacology, but also in hemodynamic regulation and vascular biology with special focus on the human placenta.
  • M. van Poppel will teach DP-iDP students how to analyze clustered datasets e. g. more than one cell culture isolated from one placenta, multiple measurements within one person) using multilevel analyses. Basic concepts such as confounding, representativeness, bias, validity and causality will be trained, as well as other relevant epidemiological methods.
  • G. Desoye will teach the students how to isolate endothelial cells and macrophages from the placenta and / or umbilical cord, introduce them to the biology of angiogenesis and help with assays of 2-D network formation and tube formation.

 

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

  • Dolores Busso, PhD (Pontifical Catholic University of Chile): Prof. Busso is an expert in animal reproduction with special focus on the impact of lipoproteins in reproductive medicine.
  • Udo Markert, MD (Clinic of Obstetrics and Gynaecology, University of Jena): Prof. Markert recently has reported a comprehensive miRNA encyclopedia of trophoblast cells and investigates with his team the function of these miRNAs on fetal development.
  • Paul Brownbill, PhD (University of Manchester): his expertise includes transplacental transfer of solute and water, the transplacental paracellular route and the regulation of fetoplacental vascular tone.

  

Industrial partners:

Amgen, Pfizer, Roche, TEV

Know-how and infrastructure of the research group:       

Christian Wadsack’s laboratory has longstanding expertise in the field of lipids / lipoproteins in pregnancy and their impact on the human placenta in normal and pathophysiological pregnancies. In order to study transport / transfer of lipids across intact placental barrier two ex vivo placental perfusion systems were assembled and experiments are running frequently with different questions in the laboratory. The laboratory uses a wide range of techniques to follow either biologicals or lipids across the human placenta including inflammatory conditions like pre-eclampsia, diabetes or antiphospholipid syndrome. All required equipment is available at the department, including a team of research nurses which provide the laboratory with placentas from the delivery room including all subject characteristics and if necessary clinical data of the women. Mass spectrometry analyses are performed at the Centre for Medical Research and the Institute of Medical and Chemical Laboratory Diagnostics, both located at the Med Uni Graz.

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

DP-iDP students will be trained in maternal and fetal lipoprotein biochemistry in early and late pregnancy which includes special techniques (ultracentrifugation and FPLC) for the isolation of the distinct HDL sub-fractions. The students will also learn how to isolate and cultivate primary cells of first-trimester and term human placentas (normal and out of placentas from pregnancy diseases), e. g. trophoblast, macrophages and arterial and venous endothelial cells. Migration and barrier assays (ECIS) will be introduced and trained in order to investigate the impact of isolated lipoproteins on placental (barrier) function. Further techniques that the students will acquire include the dually ex vivo placental perfusion system to determine the transport / transfer rate of substances across the intact placental tissue, multiplex ELISA to measure cytokines, immunofluorescence microscopy and assays to detect and characterize placenta derived microvesicles / exosomes.

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