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Forschung Gottfried Schatz Forschungszentrum

Research Gottfried Schatz Research Center Research centers and institutes Medical University of Graz

Research team Gauster

Research Focus: Reproduction, pregnancy and regeneration

PI: Martin Gauster

Focus: Inadequate placental development during early pregnancy has been associated with pregnancy complications, such as preeclampsia and intrauterine growth restriction, which may lead to an adverse outcome of pregnancy and to deleterious effects on mother and child even later in life. Thus, our current projects focus on inflammatory processes in early placental development as well as mechanisms involved in placenta-associated pregnancy pathologies.

Network: We cooperate with Desoye Gernot, Hiden Ursula, Hirschmugl Birgit, Wadsack Christian (Department of Obstetrics and Gynaecology), Cvirn Gerhard (Division of Physiological Chemistry, Otto Loewi Research Center), Giovanny Rodriguez Blanco (Klinisches Institut für Medizinische und Chemische Labordiagnostik), Julia Kargl (Division of Pharmacology, Otto Loewi Research Center), Alexander Deutsch (Klinische Abteilung für Hämatologie).

Projects

Maternal platelets and extravillous trophoblasts

Recently our published research show that in progressing pregnancy maternal platelets are partially activated at the placental surface during their passage through the placenta, and thereby release their stored platelet factors. The release of these platelet-derived factors seems to have a significant impact on the production of many important pregnancy hormones. Moreover, our new findings reveal that maternal platelets can leave the bloodstream, when entering into the placenta and apparently can leak into intercellular spaces of fetal cells that anchor the placenta to the uterine wall. Subsequent microscopic investigations suggest activation of the maternal platelets in these intercellular spaces. Based on these observations, the influence of platelet activation and the release of platelet-derived factors on fetal placental cells will be investigated in this follow-up project. The effect of the platelet- derived factors on cell differentiation and invasiveness of the placenta cells into the maternal uterine wall will be investigated in detail. These questions have not been investigated before and represent a new scientific concept that opens up novel mechanistic and therapeutic approaches for pregnancy diseases that are associated with increased platelet activation at the placental attachment zone.
Fördergeber: FWF
Laufzeit: 2022 - 2026
PI: Gauster

Placenta-educated maternal platelets (PEPs)

Platelets are small, circulating blood cells, which are built in the bone marrow. Recent biomolecular analyses of platelets suggest aberrant RNA and protein profiles under pathological conditions, including cardiovascular disease, blood cancer and solid tissue tumors. In the case of cancer, platelets have been described to be educated by tumor-released factors. This fascinating concept may be translated to pregnancy, when placenta released factors potentially modify the content and function of maternal platelets. In human pregnancy, maternal platelets show increased activity that is even more increased in the pregnancy disorder preeclampsia. To prove the concept of placenta-educated platelets, this project will study the influence of pregnancy and placenta-related factors on the fromation and content of platelets in different stages of gestation. For this purpose, platelets from healthy pregnant donors, who donated blood in all three trimesters of gestation, and those with preeclampsia, will be subjected to RNA and protein analyses. Moreover, functional assays, such as energy production or formation of aggregates of platelets with other circulating blood cells will be performed. In addition, influence of pregnancy and placenta-related factors on the formation of platelets will be elucidated in a human bone marrow cell line and a rat model. This project is of significance as it could fill a gap in our knowledge on the maternal platelet content and it may contribute to our understanding of pregnancy pathologies related to a prothrombotic state. Identification of different platelet subgroups in pregnancy, with different response to anti-platelet drugs could provide the basis for new therapeutic strategies.
Fördergeber: FWF
Laufzeit: 2025 - 2029
PI: Gauster

LYVE-1 Hofbauer cells in preeclampsia

Preeclampsia is a serious pregnancy complication characterized by the onset or worsening of high blood pressure and increased protein in the urine after the twentieth week of pregnancy. In pregnancies complicated by preeclampsia, the placenta, a vital organ for pregnancy, undergoes significant changes leading to inflammation, vascular problems, and abnormal placental tissue structure. One crucial type of cells found in the placenta, known as Hofbauer cells, are placental macrophages. These cells express a receptor called LYVE-1 and interact with hyaluronan, an important component of the connective tissue. In preeclampsia, Hofbauer cells may not function properly, potentially contributing to placental dysfunction. This joint bilateral research project aims to delve into this phenomenon by examining data from placental tissue samples and investigating how Hofbauer cells interact with other cells in the placenta. For this purpose, we are using computational methods to understand how these cells develop and change during preeclampsia. Additionally, we are conducting experiments to directly assess how Hofbauer cells affect the structure and function of placental blood vessels. This project is significant because it could fill a gap in our understanding of how Hofbauer cells regulate placental tissue structure, especially in the context of preeclampsia. By gaining insights into these processes, we hope to advance our understanding of placental health and potentially identify new therapeutic targets for treating preeclampsia.
Fördergeber: FWF
Laufzeit: 2024 - 2027
PI: Gauster

Trophoblastic anticoagulant proteins at the implantation front

Human placentation depends on sufficient invasion of trophoblasts into the endometrium under local anticoagulant conditions. Invovled anticoagulant factors must be tightly controlled with respect to the time window and location of their expression at the embryo implantation site. However, a detailed characterization of the human trophoblastic anticoagulant machinery during a very early stage of placentation does not yet exist. Hence, this project’s results are expected to give new insight into the spatial-temporal expression pattern of the human trophoblastic anticoagulant machinery at the implantation site, and the trophoblastic anticoagulant machinery in cases of recurrent miscarriage.
Fördergeber: European Commission / HORIZON-MSCA-DN
Laufzeit: 2025 - 2028
PI: Gauster

Invasive properties of trophoblast subtypes during implantation and early placentation

So far, the processes during implantation and early placentation in the human are mostly unclear. Especially, the knowledge on the behavior of the trophectoderm-derived first trophoblast (mononuclear as well as syncytial) is mostly based on animal studies or few images from archival specimens. Hence, this project’s results are expected to give new insight into the mechanisms of blastocyst penetration through the uterine epithelium by using lightsheet microscopy to develop 3D images of the invasion process. Moreover, the necessity to form an early invasive syncytiotrophoblast for human implantation will be challenged by using confocal microscopy and electron microscopy.
Fördergeber: European Commission / HORIZON-MSCA-DN
LAufzeit: 12025 - 2028
PI: Huppertz

LAMB3 – DAG1 axis in endoglandular trophoblast invasion, FWF

Women in Austria currently wish to have at least 2 children on average, but unfortunately many suffer from fertility problems in the first few weeks of pregnancy and even lose their child very early on. Science cannot yet help here, as the basic processes involved in human implantation and placenta development in humans are still largely unknown. During human pregnancy, the fetus is nourished with maternal blood via the placenta. However, this so-called uteroplacental blood flow only starts from the 4th month of pregnancy. Before that, the fetus is nourished by secretions from the glands in the mother`s uterine lining. Only in recent years has it been discovered that during placental development, fetal cells from the placenta invade these uterine glands, thereby connect the glands with the placenta and thus enable the glandular secretions to reach the fetus. It is likely that the role of the uterine glands and their invasion by fetal cells in maintaining a healthy pregnancy has been underestimated. Also, the factors that may dictate this invasion pattern and thus influence reproductive success are still unknown. We want to better understand how these invading fetal cells interact with the maternal uterine glands, potentially contributing to complications in fertility and early pregnancy. However, research into human reproduction poses a particular challenge. Aside from ethical concerns, processes such as implantation and subsequent placentation differ significantly between animals and humans. The applicant has invented novel in vitro model systems for early placenta development. they are used to identify biomarkers, investigate their potential contribution to early placental development, evaluate treatment options and predict response with classical laboratory methods such as histology, molecular biology together with modern bioinformatics. Thereby a potential contribution of these biomarkers to early pregnancy will be investigated. This project offers the opportunity to gain insights into fertility issues and pregnancy-related diseases and thus makes an important contribution to the prevention of diseases that affect women.
Fördergeber: FWF
Laufzeit: 2024 - 2028
PI: Moser

LYMPHO-CHECK: Bioinformatik und Data-Mining in der Lymphomforschung

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in the western world. While immune checkpoint blockade therapy is in clinical practice for a number of cancer types, the response rates for B cell lymphomas remain disappointingly low. Importantly, immune evasive mechanisms are still poorly investigated in B cell lymphomas,which has impeded the progress in developing new therapeutic approaches targeting the lymphoma immune landscape. This bioinformatics project aims to address this gap by investigating the immunomodulatory effects of the NR4A1/p53 axis, two pivotal transcription factors and tumour suppressors.
Fördergeber: FWF
Laufzeit: 2024 - 2029
PI: Feichtinger

Completed Projects

The role of adhering maternal platelets on villous trophoblast

Adhering maternal platelets represent an underappreciated source of modulating factors, which could affect villous trophoblast and its cross-talk with maternal circulating blood cells. In this project, the hypothesis is tested whether platelet-derived factors affect proliferation, differentiation and the endocrine activity of trophoblasts, and whether they can activate maternal immune cells that pass the placental intervillous space.
Duration: 2017-2021
Funded by: FWF

The role of Angiotensin II on placental fractalkine

Angiotensin acts on angiotensin receptors located on many organs including human placenta. Angiotensin has been suggested to function as an inflammatory mediator by inducing synthesis of proinflammatory molecules. Amongst these, the chemokine fractalkine has recently attracted increasing attention due to its dual nature, existing both as cell-bound and soluble form. In this project the hypothesis is tested whether or not angiotensin II can stimulate the synthesis and release of fractalkine in human placenta and moreover, whether this stimulatory effect promotes adhesion and activation of a certain subset of maternal white blood cells.
Duration: 2017-2021
Funded by: FWF
Project partner: Florian Herse (Charité / MDC Berlin)

Flow-mediated modulation of villous trophoblast physiology

In this study, the relationship between the intensity of fluid shear stress and the biological response of the villous trophoblast layer will be investigated. Thus, the hypothesis is tested whether alterations in flow rate affects trophoblast turnover, morphology, metabolism, endocrine activity and the inflammatory response. The overarching aim is addressed by three interconnected work packages, including flow culture experiments with a trophoblast cell line, primary trophoblasts and placental explants from human first trimester of pregnancy.
Duration: 2020-2023
Funded by: OeNB

Placental CD39 and CD73 in human pregnancy

Extracellular ATP serves as an important signalling molecule that modulates several pathological effects in the settings of inflammation, platelet activation and thrombosis. Extracellular ATP is deactivated by conversion into AMP and subsequently into adenosine by the two major nucleotide-metabolizing enzymes CD39 and CD73. In this project, the hypothesis is tested whether CD39 and CD73 are expressed in human placenta from very early phase onwards to term of gestation, and whether they are deregulated in response to pro-inflammatory cytokines, to reduced oxygen supply and increased mechanical shear forces.
Duration: 2020-2024
Funded by: FWF

Maternal platelet activation and the placental endocrine activity

This study investigates the localization and activation of maternal platelets in human first trimester placenta. Moreover, focus is set on the influence of maternal platelets and their released factors on different trophoblast subtypes and their endocrine activity. This study will provide additional insight into maternal-fetal interactions and how exaggerated platelet activation can contribute to pregnancy pathologies.
Duration: 2018-2022
Funded by: FWF

Placental explant culture 2.0: Flow culture better mimics the in vivo situation in preeclampsia

Preeclampsia is a pregnancy syndrome with unknown etiology, where placental degeneration may result in the release of pro-inflammatory vesicles into maternal blood. The vesicles affect the maternal vascular system resulting in clinical symptoms of the mother. To elucidate quality and quantity of particles and their effect on the maternal endothelium, we established a novel flow culture system for placental explants simulating various health conditions of pregnancy. This enables the analysis of the effect of released placental particles on maternal endothelial cells under constant fluid flow.
Duration: 2018-2022
Funded by: FWF

Division of Cell Biology, Histology and Embryology

Assoz.-Prof. Priv.-Doz. Mag. Dr.
Martin Gauster

T: +43 316 385 71896

E: martin.gauster(at)medunigraz.at

Research profile