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7. Ex vivo dual perfusion of an isolated human placenta cotyledon: Towards protocol standardization and improved inter-centre comparability

Author

Schneider, Henning, Albrecht, Christiane, Ahmed, Mahmoud S., Broekhuizen, Michelle, Aengenheister, Leonie, Buerki-Thurnherr, Tina, Danser, A.H. Jan, Gil, Sophie, Hansson, Stefan R., Greupink, Rick, Lewis, Rohan M., Markert, Udo R., Mathiesen, Line, Powles-Glover, Nicola, Wadsack, Christian, and Brownbill, Paul

Published
2022
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17. TGFβ signalling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy.

Author

Mercnik, Monika Horvat, Schliefsteiner, Carolin, Sanchez-Duffhues, Gonzalo, and Wadsack, Christian

Subjects
PLACENTA diseases, ENDOTHELIUM diseases, TRANSFORMING growth factors-beta, GROWTH differentiation factors, PREGNANCY complications, BONE morphogenetic proteins, VASCULAR remodeling
Abstract

BACKGROUND The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFβ) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFβ signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFβ signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFβ signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFβ is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta. OBJECTIVE AND RATIONALE This comprehensive review aims to explore and elucidate the roles of the major members of the TGFβ superfamily, including TGFβs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy. SEARCH METHODS A literature search was carried out using PubMed and Google Scholar, searching terms: 'TGF signalling preeclampsia', 'pregnancy TGF signalling', 'preeclampsia tgfβ', 'preeclampsia bmp', 'preeclampsia gdf', 'preeclampsia activin', 'endoglin preeclampsia', 'endoglin pregnancy', 'tgfβ signalling pregnancy', 'bmp signalling pregnancy', 'gdf signalling pregnancy', 'activin signalling pregnancy', 'Hofbauer cell tgfβ signalling', 'placental macrophages tgfβ', 'endothelial cells tgfβ', 'endothelium tgfβ signalling', 'trophoblast invasion tgfβ signalling', 'trophoblast invasion Smad', 'trophoblast invasion bmp', 'trophoblast invasion tgfβ', 'tgfβ preeclampsia', 'tgfβ placental development', 'TGFβ placental function', 'endothelial dysfunction preeclampsia tgfβ signalling', 'vascular remodelling placenta TGFβ', 'inflammation pregnancy tgfβ', 'immune response pregnancy tgfβ', 'immune tolerance pregnancy tgfβ', 'TGFβ pregnancy NK cells', 'bmp pregnancy NK cells', 'bmp pregnancy tregs', 'tgfβ pregnancy tregs', 'TGFβ placenta NK cells', 'TGFβ placenta tregs', 'NK cells preeclampsia', 'Tregs preeclampsia'. Only articles published in English until 2023 were used. OUTCOMES A comprehensive understanding of TGFβ signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFβ ligands contribute to the proper functioning of a healthy maternal–foetal interface. However, dysregulation of TGFβ signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFβ signalling. WIDER IMPLICATIONS The dysregulation of TGFβ signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFβ signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Maternal Angiotensin Increases Placental Leptin in Early Gestation via an Alternative Renin-Angiotensin System Pathway: Suggesting a Link to Preeclampsia

Author

Nonn, Olivia, Fischer, Cornelius, Geisberger, Sabrina, El-Heliebi, Amin, Kroneis, Thomas, Forstner, Désirée, Desoye, Gernot, Staff, Anne Cathrine, Sugulle, Meryam, Dechend, Ralf, Pecks, Ulrich, Kollmann, Martina, Stern, Christina, Cartwright, Judith E., Whitley, Guy S., Thilaganathan, Basky, Wadsack, Christian, Huppertz, Berthold, Herse, Florian, and Gauster, Martin

Published
2021
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32. Gestational Hypertension and High-Density Lipoprotein Function:An Explorative Study in Overweight/Obese Women of the DALI Cohort

Author

Stadler, Julia T., van Poppel, M. N. M., Christoffersen, Christina, Hill, David, Wadsack, Christian, Simmons, David, Desoye, Gernot, Marsche, Gunther, DALI Core Investigator Grp, Stadler, Julia T., van Poppel, M. N. M., Christoffersen, Christina, Hill, David, Wadsack, Christian, Simmons, David, Desoye, Gernot, Marsche, Gunther, and DALI Core Investigator Grp

Abstract

Gestational hypertension (GHTN) is associated with an increased cardiovascular risk for mothers and their offspring later in life. High-density lipoproteins (HDL) are anti-atherogenic by promoting efflux of cholesterol from macrophages and suppression of endothelial cell activation. Functional impairment of HDL in GHTN-complicated pregnancies may affect long-term health of both mothers and offspring. We studied functional parameters of maternal and neonatal HDL in 192 obese women (pre-pregnancy BMI >= 29), who were at high risk for GHTN. Maternal blood samples were collected longitudinally at

Published
2023

33. CD39 abrogates platelet-derived factors induced IL-1β expression in the human placenta

Author

Forstner, Désirée, primary, Guettler, Jacqueline, additional, Brugger, Beatrice A., additional, Lyssy, Freya, additional, Neuper, Lena, additional, Daxboeck, Christine, additional, Cvirn, Gerhard, additional, Fuchs, Julia, additional, Kraeker, Kristin, additional, Frolova, Alina, additional, Valdes, Daniela S., additional, Stern, Christina, additional, Hirschmugl, Birgit, additional, Fluhr, Herbert, additional, Wadsack, Christian, additional, Huppertz, Berthold, additional, Nonn, Olivia, additional, Herse, Florian, additional, and Gauster, Martin, additional

Published
2023
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38. Inhibition of diacylglycerol lipase β modulates lipid and endocannabinoid levels in the ex vivo human placenta

Author

Berger, Natascha, primary, van der Wel, Tom, additional, Hirschmugl, Birgit, additional, Baernthaler, Thomas, additional, Gindlhuber, Juergen, additional, Fawzy, Nermeen, additional, Eichmann, Thomas, additional, Birner-Gruenberger, Ruth, additional, Zimmermann, Robert, additional, van der Stelt, Mario, additional, and Wadsack, Christian, additional

Published
2023
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49. Ex vivo dual perfusion of an isolated human placenta cotyledon:Towards protocol standardization and improved inter-centre comparability

Author

Schneider, Henning, Albrecht, Christiane, Ahmed, Mahmoud S., Broekhuizen, Michelle, Aengenheister, Leonie, Buerki-Thurnherr, Tina, Danserf, A. H. Jan, Gil, Sophie, Hansson, Stefan R., Greupink, Rick, Lewis, Rohan M., Markert, Udo R., Mathiesen, Line, Powles-Glover, Nicola, Wadsack, Christian, Brownbill, Paul, Schneider, Henning, Albrecht, Christiane, Ahmed, Mahmoud S., Broekhuizen, Michelle, Aengenheister, Leonie, Buerki-Thurnherr, Tina, Danserf, A. H. Jan, Gil, Sophie, Hansson, Stefan R., Greupink, Rick, Lewis, Rohan M., Markert, Udo R., Mathiesen, Line, Powles-Glover, Nicola, Wadsack, Christian, and Brownbill, Paul

Abstract

Since the full development of the ex vivo dual perfusion model of the human placenta cotyledon, the technique has provided essential insight into how nutrients, lipids, gases, immunoglobulins, endocrine agents, pharma-ceuticals, chemicals, nanoparticles, micro-organisms and parasites might traverse the maternofetal barrier. Additionally, the model has been instrumental in gaining a better understanding of the regulation of vascular tone, endocrinology and metabolism within this organ. The human placenta is unique amongst species in its anatomy and transfer modalities. This orthologous diversity therefore requires an appropriate consideration of placental transfer rates of compounds, particles and micro-organisms specific to humans. Different research centres have adapted this model with a wide variation in perfusion parameters, including in the establishment of perfusion, perfusate composition, gassing regime, cannulation method, flow rates, perfused tissue mass, and also in the application of quality control measures. The requirement to harmonise and stan-dardise perfusion practice between centres is largely driven by the need to obtain consistency in our under -standing of placental function, but also in the qualification of the model for acceptance by regulatory agencies in drug and toxicology testing. A pilot study is proposed, aiming to describe how existing inter-centre variation in perfusion methodology affects placental metabolism, protein synthesis, oxygen consumption, the materno-fetal transfer of key molecular markers, and placental structure.

Published
2022

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