Publications by authors named "Berthold Huppertz"

127 Publications

Reduced Placental CD24 in Preterm Preeclampsia Is an Indicator for a Failure of Immune Tolerance.

Int J Mol Sci 2021 Jul 28;22(15). Epub 2021 Jul 28.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6/II, 8010 Graz, Austria.

Introduction: CD24 is a mucin-like glycoprotein expressed at the surface of hematopoietic and tumor cells and was recently shown to be expressed in the first trimester placenta. As it was postulated as an immune suppressor, CD24 may contribute to maternal immune tolerance to the growing fetus. Preeclampsia (PE), a major pregnancy complication, is linked to reduced immune tolerance. Here, we explored the expression of CD24 in PE placenta in preterm and term cases.

Methods: Placentas were derived from first and early second trimester social terminations (N = 43), and third trimester normal term delivery (N = 67), preterm PE (N = 18), and preterm delivery (PTD) (N = 6). CD24 expression was determined by quantitative polymerase chain reaction (qPCR) and Western blotting. A smaller cohort included 3-5 subjects each of term and early PE, and term and preterm delivery controls analyzed by immunohistochemistry.

Results: A higher expression (2.27-fold) of CD24 mRNA was determined in the normal term delivery compared to first and early second trimester cases. The mRNA of preterm PE cases was only higher by 1.31-fold compared to first and early second trimester, while in the age-matched PTD group had a fold increase of 5.72, four times higher compared to preterm PE. The delta cycle threshold (ΔCt) of CD24 mRNA expression in the preterm PE group was inversely correlated with gestational age (r = 0.737) and fetal size (r = 0.623), while correlation of any other group with these parameters was negligible. Western blot analysis revealed that the presence of CD24 protein in placental lysate of preterm PE was significantly reduced compared to term delivery controls ( = 0.026). In immunohistochemistry, there was a reduction of CD24 staining in villous trophoblast in preterm PE cases compared to gestational age-matched PTD cases ( = 0.042). Staining of PE cases at term was approximately twice higher compared to preterm PE cases ( = 0.025) but not different from normal term delivery controls.

Conclusion: While higher CD24 mRNA expression levels were determined for normal term delivery compared to earlier pregnancy stages, this expression level was found to be lower in preterm PE cases, and could be said to be linked to reduced immune tolerance in preeclampsia.
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http://dx.doi.org/10.3390/ijms22158045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348750PMC
July 2021

Placental Villous Explant Culture 2.0: Flow Culture Allows Studies Closer to the In Vivo Situation.

Int J Mol Sci 2021 Jul 12;22(14). Epub 2021 Jul 12.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.

During pregnancy, freely floating placental villi are adapted to fluid shear stress due to placental perfusion with maternal plasma and blood. In vitro culture of placental villous explants is widely performed under static conditions, hoping the conditions may represent the in utero environment. However, static placental villous explant culture dramatically differs from the in vivo situation. Thus, we established a flow culture system for placental villous explants and compared commonly used static cultured tissue to flow cultured tissue using transmission and scanning electron microscopy, immunohistochemistry, and lactate dehydrogenase (LDH) and human chorionic gonadotropin (hCG) measurements. The data revealed a better structural and biochemical integrity of flow cultured tissue compared to static cultured tissue. Thus, this new flow system can be used to simulate the blood flow from the mother to the placenta and back in the most native-like in vitro system so far and thus can enable novel study designs.
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http://dx.doi.org/10.3390/ijms22147464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308011PMC
July 2021

Molecular characteristics of established trophoblast-derived cell lines.

Placenta 2021 05 4;108:122-133. Epub 2021 Mar 4.

Placenta Lab, Department of Obstetrics, Jena University Hospital, 07747, Jena, Germany. Electronic address:

Introduction: Research on human placental development and function lacks a conclusive in vivo model. To investigate the intracellular molecular mechanisms in trophoblast cells, different cell lines have been established during the last decades. So far, none of these accomplishes all features of primary trophoblast, thus their suitability as well as the transferability of the results has been discussed. The aim of this study is to assess molecular markers and features matching different trophoblast subpopulations in trophoblastic cell lines to provide orientation on their suitability and relevance for distinct research questions.

Methods: The commonly used trophoblastic cell lines, BeWo, JEG-3, HTR-8/SVneo, AC1-M59, AC1-M32, ACH-3P and Swan71 were selected. qPCR and immunoblotting were used to determine expression of characteristic molecular markers. C14MC, C19MC and miR-371-3 miRNA expression were investigated by real time PCR. Proliferation, migration and network stabilization assays were performed. Hormone secretion was determined by chemiluminescent-immunoassays. DNA profiles were obtained by Short Tandem Repeat (STR)-genotyping.

Results: Immortalized cell lines differ from choriocarcinoma-derived ones in the expression of HLA-G, E-cadherin, N-cadherin, VE-cadherin, cadherin-11, cytokeratin 7, vimentin, ADAM12 and PRG2. Compared to choriocarcinoma-derived cell lines, expression of C19MC and hormone secretion were almost absent in immortalized cell lines. Conversely, they express C14MC and exhibit higher migration and network stabilization.

Discussion: The data presented will help justify the use of a cell line to evaluate distinct features of trophoblast biology and pathology. In general, characteristics and markers of choriocarcinoma derived cell lines seem to be more similar to in vivo trophoblast than immortalized cell lines and thus might be regarded as more suitable models.
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http://dx.doi.org/10.1016/j.placenta.2021.02.022DOI Listing
May 2021

The endogenous exposome of the pregnant mother: Placental extracellular vesicles and their effect on the maternal system.

Mol Aspects Med 2021 Feb 18:100955. Epub 2021 Feb 18.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria. Electronic address:

During pregnancy, there is an intense crosstalk between mother and placenta. During the entire time of pregnancy, the maternal system deals with a huge amount of foreign (fetal) material released from the placenta, which can be referred to as placental exposome. Besides the release of hormones and growth factors, the placenta releases a variety of extracellular vesicles into maternal blood. These vesicles contain specific molecules including proteins, lipids, DNA as well as miRNA, all of which may have specific sites and modes of action on maternal cells. During normal pregnancy, the fine-tuning of factors and vesicles helps maintaining a viable and healthy pregnancy. However, in pregnancy pathologies such as preeclampsia, quantity and quality of the placenta-derived vesicles are altered leading to a deleterious effect on the maternal vascular system. This review focuses on the different types of placenta-derived extracellular vesicles in pregnancy with special emphasis on the interplay between these placental vesicles and the maternal system. Additionally, it displays new techniques and ideas for the analysis of the placental exposome with placental extracellular vesicles as a key aspect.
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http://dx.doi.org/10.1016/j.mam.2021.100955DOI Listing
February 2021

Perinatal Derivatives: Where Do We Stand? A Roadmap of the Human Placenta and Consensus for Tissue and Cell Nomenclature.

Front Bioeng Biotechnol 2020 17;8:610544. Epub 2020 Dec 17.

Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.

Progress in the understanding of the biology of perinatal tissues has contributed to the breakthrough revelation of the therapeutic effects of perinatal derivatives (PnD), namely birth-associated tissues, cells, and secreted factors. The significant knowledge acquired in the past two decades, along with the increasing interest in perinatal derivatives, fuels an urgent need for the precise identification of PnD and the establishment of updated consensus criteria policies for their characterization. The aim of this review is not to go into detail on preclinical or clinical trials, but rather we address specific issues that are relevant for the definition/characterization of perinatal cells, starting from an understanding of the development of the human placenta, its structure, and the different cell populations that can be isolated from the different perinatal tissues. We describe where the cells are located within the placenta and their cell morphology and phenotype. We also propose nomenclature for the cell populations and derivatives discussed herein. This review is a joint effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the processing and characterization and clinical application of PnD.
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http://dx.doi.org/10.3389/fbioe.2020.610544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773933PMC
December 2020

IJMS Special Issue "Molecular and Cellular Mechanisms of Preeclampsia"-Editorial.

Int J Mol Sci 2020 Jul 7;21(13). Epub 2020 Jul 7.

Professor of Cell Biology, Chair, Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6/II, 8010 Graz, Austria.

Over the last few decades, massive research efforts have been put into deciphering the etiology of the pregnancy pathology preeclampsia[...].
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http://dx.doi.org/10.3390/ijms21134801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369901PMC
July 2020

Traditional and New Routes of Trophoblast Invasion and Their Implications for Pregnancy Diseases.

Int J Mol Sci 2019 Dec 31;21(1). Epub 2019 Dec 31.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria.

Historically, invasion of placental trophoblasts was thought to be extremely specific, only invading into the connective tissues of the maternal uterus and finally reaching and transforming the uterine spiral arteries. Only recently, identification of new routes of trophoblast invasion into different structures of the maternal uterus has been achieved. Thorough morphological analysis has resulted in the identification of trophoblasts invading into glands, veins, and lymph vessels of the uterine wall. These new routes pave the way for a re-evaluation of trophoblast invasion during normal placental development. Of course, such new routes of trophoblast invasion may well be altered, especially in pregnancy pathologies such as intra-uterine growth restriction, preeclampsia, early and recurrent pregnancy loss, stillbirth, and spontaneous abortion. Maybe one or more of these pregnancy pathologies show alterations in different pathways of trophoblast invasion, and, thus, etiologies may need to be redefined, and new therapies may be developed.
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http://dx.doi.org/10.3390/ijms21010289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981830PMC
December 2019

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis.

J Mol Med (Berl) 2020 02 20;98(2):193-207. Epub 2019 Dec 20.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, II, 8010, Graz, Austria.

During histiotrophic nutrition of the embryo, maternal platelets may be the first circulating maternal cells that find their way into the placental intervillous space through narrow intertrophoblastic gaps within the plugs of spiral arteries. Activation of platelets at the maternal-fetal interface can influence trophoblast behavior and has been implicated in serious pregnancy pathologies. Here, we show that platelet-derived factors impaired expression and secretion of the human chorionic gonadotropin beta-subunit (βhCG) in human first trimester placental explants and the trophoblast cell line BeWo. Impaired βhCG synthesis was not the consequence of hampered morphological differentiation, as assessed by analysis of differentiation-associated genes and electron microscopy. Platelet-derived factors did not affect intracellular cAMP levels and phosphorylation of CREB, but activated Smad3 and its downstream-target plasminogen activator inhibitor (PAI)-1 in forskolin-induced BeWo cell differentiation. While TGF-β type I receptor inhibitor SB431542 did not restore impaired βhCG production in response to platelet-derived factors, Smad3 inhibitor SIS3 interfered with CREB activation, suggesting an interaction of cAMP/CREB and Smad3 signaling. Sequestration of transcription co-activators CBP/p300, known to bind both CREB and Smad3, may limit βhCG production, since CBP/p300 inhibitor C646 significantly restricted its forskolin-induced upregulation. In conclusion, our study suggests that degranulation of maternal platelets at the early maternal-fetal interface can impair placental βhCG production, without substantially affecting morphological and biochemical differentiation of villous trophoblasts. KEY MESSAGES: Maternal platelets can be detected on the surface of the placental villi and in intercellular gaps of trophoblast cell columns from gestational week 5 onwards. Platelet-derived factors impair hCG synthesis in human first trimester placenta. Platelet-derived factors activate Smad3 in trophoblasts. Smad3 inhibitor SIS3 interferes with forskolin-induced CREB signaling. Sequestration of CBP/p300 by activated Smad3 may limit placental hCG production.
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http://dx.doi.org/10.1007/s00109-019-01866-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007904PMC
February 2020

Galectin 13 (PP13) Facilitates Remodeling and Structural Stabilization of Maternal Vessels during Pregnancy.

Int J Mol Sci 2019 Jun 29;20(13). Epub 2019 Jun 29.

Hylabs Ltd., Rehovot, 7670606 and TeleMarpe Ltd., 6908742 Tel Aviv, Israel.

Galectins regulate cell growth, proliferation, differentiation, apoptosis, signal transduction, mRNA splicing, and interactions with the extracellular matrix. Here we focus on the galectins in the reproductive system, particularly on a group of six galectins that first appears in anthropoid primates in conjunction with the evolution of highly invasive placentation and long gestation. Of these six, placental protein 13 (PP13, galectin 13) interacts with glycoproteins and glycolipids to enable successful pregnancy. PP13 is related to the development of a major obstetric syndrome, preeclampsia, a life-threatening complication of pregnancy which affects ten million pregnant women globally. Preeclampsia is characterized by hypertension, proteinuria, and organ failure, and is often accompanied by fetal loss and major newborn disabilities. PP13 facilitates the expansion of uterine arteries and veins during pregnancy in an endothelial cell-dependent manner, via the eNOS and prostaglandin signaling pathways. PP13 acts through its carbohydrate recognition domain that binds to sugar residues of extracellular and connective tissue molecules, thus inducing structural stabilization of vessel expansion. Further, decidual PP13 aggregates may serve as a decoy that induces white blood cell apoptosis, contributing to the mother's immune tolerance to pregnancy. Lower first trimester PP13 level is one of the biomarkers to predict the subsequent risk to develop preeclampsia, while its molecular mutations/polymorphisms that are associated with reduced PP13 expression are accompanied by higher rates of preeclampsia We propose a targeted PP13 replenishing therapy to fight preeclampsia in carriers of these mutations.
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http://dx.doi.org/10.3390/ijms20133192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651626PMC
June 2019

Placental protein 13 (PP13) stimulates rat uterine vessels after slow subcutaneous administration.

Int J Womens Health 2019 27;11:213-222. Epub 2019 Mar 27.

Faculty of Pharmaceutical Sciences, School of Health Science, University of Iceland, Reykjavik, Iceland,

Introduction: Reduced concentrations of placental protein 13 (PP13) during the first trimester of human pregnancy are associated with elevated risk for the subsequent development of preeclampsia, which is one of the deadliest obstetrical complications of pregnancy. Previous studies by our group have shown that PP13 lowers blood pressure in pregnant rats, increases the size and weight of pups and placentas, and induces vasodilation of resistance arteries through endothelial signaling pathways involving endothelial nitric oxid synthase and prostaglandin.

Methods: In the present study, the effect of PP13 was investigated in nonpregnant female Sprague Dawley rats (n=27). Osmotic pumps were surgically implanted subcutaneously that released a constant dose of PP13 or saline over 7 days. Most animals were sacrificed 6 days after the end of PP13 release (on day 13), while some were sacrificed immediately at the end of day 7 (the last PP13 release day), to compare the short- and long-term impact of PP13 on vessels' growth and size.

Results: The uterine vessels were significantly expanded in the group exposed to recombinant PP13 (rPP13) compared to the control (saline) group. Both veins and arteries were significantly expanded by rPP13 with a more pronounced effect after 13 days compared to the corresponding vessels after 7 days. Furthermore, the long-term effect of treatment by rPP13 was more pronounced in the veins compared to the corresponding arteries. The effect of a PP13 variant with a histidine-tag (His-PP13) remained the same between 7 and 13 days.

Conclusion: In conclusion, PP13 might play a key role in the expansive remodeling of the uterine vessels, reflecting what would happen if the rat was pregnant, preparing the uterine vascu-lature for the increase in uteroplacental blood flow, which is necessary for normal pregnancy. We suggest that PP13 could act by NO signaling pathways, a hypothesis that requires future study.
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http://dx.doi.org/10.2147/IJWH.S188303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443218PMC
March 2019

Amnion-derived mesenchymal stem cells improve viability of endothelial cells exposed to shear stress in ePTFE grafts.

Int J Artif Organs 2019 Feb 26;42(2):80-87. Epub 2018 Dec 26.

1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.

Purpose:: Blood vessel reconstruction is an increasing need of patients suffering from cardiovascular diseases. For the development of microvascular prostheses, efficient endothelialization is mandatory to prevent graft occlusion. Here, we assessed the impact of amnion-derived mesenchymal stem/stromal cells (hAMSC), known for their important angiogenic potential, on the integrity and stability of endothelial cells exposed to shear stress in vascular grafts.

Methods:: Human placental endothelial cells (hPEC) were cultured at the inner surface of an expanded polytetrafluoroethylene (ePTFE) graft positioned within a bioreactor and exposed to a minimal shear stress of 0.015 dyne/cm or a physiological shear stress of 0.92 dyne/cm. hAMSC attached to the outer graft surface were able to interact with human placental endothelial cells by paracrine factors.

Results:: Microscopical analysis and evaluation of glucose/lactate metabolism evidenced successful cell seeding of the graft: hPEC formed a stable monolayer, hAMSC showed a continuous growth during 72 h incubation. hAMSC improved the viability of hPEC exposed to 0.015 dyne/cm as shown by a decreased lactate dehydrogenase release of 13% after 72 h compared to hPEC single culture. The viability-enhancing effect of hAMSC on hPEC was further improved by 13% under physiological shear stress. Angiogenesis array analysis revealed that hPEC exposed to physiological shear stress and hAMSC co-culture reduced the secretion of angiogenin, GRO, MCP-1, and TIMP-2.

Conclusion:: hAMSC exerted best survival-enhancing effects on hPEC under exposure to physiological shear stress and modulated endothelial function by paracrine factors. Our data support further studies on the development of grafts functionalized with hAMSC-derived secretomes to enable fast clinical application.
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http://dx.doi.org/10.1177/0391398818815470DOI Listing
February 2019

Biology of preeclampsia: Combined actions of angiogenic factors, their receptors and placental proteins.

Biochim Biophys Acta Mol Basis Dis 2020 02 13;1866(2):165349. Epub 2018 Dec 13.

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria. Electronic address:

Although massive efforts have been undertaken to elucidate the etiology of the pregnancy syndrome preeclampsia, its developmental origin remains a mystery. Most efforts of the last decade have focused on biomarkers to predict and/or diagnose preeclampsia, including the anti-angiogenic factor sFlt-1 (soluble fms-like tyrosin kinase-1), the angiogenic factor PGF (placental growth factor) and PP13 (placental protein 13). The origins of these marker proteins are still under debate, and so far their actions have only been describe separate from each other. This study will focus on the origins and actions of all three markers during pregnancy and outside pregnancy and will describe a scenario where all three markers act synergistically to rescue the mother from the deleterious effects of the debris that is released from the placenta during preeclampsia. This more holistic approach may open new avenues to think about maternal-fetal interactions and putative therapies.
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http://dx.doi.org/10.1016/j.bbadis.2018.11.024DOI Listing
February 2020

An updated view on the origin and use of angiogenic biomarkers for preeclampsia.

Expert Rev Mol Diagn 2018 12 14;18(12):1053-1061. Epub 2018 Nov 14.

a Division of Cell Biology, Histology and Embryology , Gottfried Schatz Research Center, Medical University of Graz , Graz , Austria.

: The last decade has seen massive efforts towards the identification and the potential use of predictive biomarkers for the pregnancy pathology preeclampsia. The angiogenic factors sFlt-1 and placental growth factor (PGF) have been in focus and have been massively supported. : This review describes preeclampsia and intra-uterine growth restriction (IUGR), focusing on sFlt-1 and PGF, their sources during and outside pregnancy and the application of these markers in diseases outside pregnancy. Finally, the specificity of the angiogenic markers for preeclampsia is discussed. : The admixture of the two independent syndromes preeclampsia and IUGR has not helped in identifying the etiologies of either. Rather, it has made the search for new markers and pathways much more complicated as has the constriction on the angiogenic markers. The current markers sFlt-1 and PGF have a clear value once an adverse outcome is diagnosed but are not specific for preeclampsia. Also, they are mostly derived from the maternal vascular system rather than the placenta and are already in use as markers outside pregnancy. A new holistic approach using disease maps and interoperable workflows based on topic-related big data will help in broadening our understanding of the etiology of preeclampsia and hence, develop new markers and therapies.
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http://dx.doi.org/10.1080/14737159.2018.1546579DOI Listing
December 2018

Impact of vitamin D and vitamin D receptor on the trophoblast survival capacity in preeclampsia.

PLoS One 2018 8;13(11):e0206725. Epub 2018 Nov 8.

Department of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.

Background: Preeclampsia and intra-uterine growth restriction (IUGR) are major health problems during pregnancy affecting both mother and child. Defective placental development and failure of trophoblast differentiation during pregnancy are important aspects in the pathogenesis of both syndromes. Recent studies have shown that autophagy is involved in the trophoblast survival capacity. As vitamin D has a central role in many cellular processes, we studied the relation of vitamin D and autophagy in those processes of preeclampsia and IUGR.

Methods: Serum and placental samples from four groups of cases; normal term, IUGR, early-onset and late-onset preeclampsia, were analyzed for 25(OH)D vitamin D, sFLT1, PGF, LGALS13 in serum and vitamin D receptor (VDR), MAP1LC3B and BECN1 in placental tissues.

Results: There was a significant difference in the sFLT1/PGF ratio in preeclamptic cases compared to controls and IUGR. There was a significant difference between these groups in the MAP1LC3B/BECN1 ratio as marker of the trophoblast survival capacity with a significantly reduced ratio in villous trophoblast of early-onset preeclampsia. Maternal vitamin D deficiency was found in all pathological pregnancies combined with significantly reduced staining levels of placental VDR in IUGR. Finally, there was a strong and significant negative correlation between the survival capacity (MAP1LC3B/BECN1) and both maternal vitamin D and placental VDR in the preeclampsia groups.

Conclusion: Vitamin D and intracellular VDR are strongly related to the trophoblast survival capacity in preeclampsia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206725PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226106PMC
April 2019

Human trophoblast invasion: new and unexpected routes and functions.

Histochem Cell Biol 2018 Oct 26;150(4):361-370. Epub 2018 Jul 26.

Department of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6/II, 8010, Graz, Austria.

Until recently, trophoblast invasion during human placentation was characterized by and restricted to invasion into uterine connective tissues and the uterine spiral arteries. The latter was explained to connect the arteries to the intervillous space of the placenta and to guarantee the blood supply of the mother to the placenta. Today, this picture has dramatically changed. Invasion of endoglandular trophoblast into uterine glands, already starting at the time of implantation, enables histiotrophic nutrition of the embryo prior to perfusion of the placenta with maternal blood. This is followed by invasion of endovenous trophoblasts into uterine veins to guarantee the drainage of fluids from the placenta back into the maternal circulation throughout pregnancy. In addition, invasion of endolymphatic trophoblasts into the lymph vessels of the uterus has been described. Only then, invasion of endoarterial trophoblasts into spiral arteries takes place, enabling hemotrophic nutrition of the fetus starting with the second trimester of pregnancy. This new knowledge paves the way to identify changes that may occur in pathological pregnancies, from tubal pregnancies to recurrent spontaneous abortions.
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http://dx.doi.org/10.1007/s00418-018-1699-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153604PMC
October 2018

Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits.

Drug Des Devel Ther 2018 3;12:1977-1983. Epub 2018 Jul 3.

Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, Reykjavik, Iceland,

Introduction: Human placental protein 13 (PP13) is a galectin predominantly expressed by the placenta. Low serum concentrations of PP13 in early pregnancy indicate a higher risk of developing preeclampsia.

Methods: The pharmacokinetic disposition and bioavailability of PP13 were determined by single intravenous and subcutaneous administration to 12 healthy New Zealand White rabbits. The serum pharmacokinetic values were determined by enzyme-linked immunosorbent assay, and are best described by a two-compartment model.

Results: Both volume of distribution and the area under the curve were dose dependent for the intravenous group (<0.01). PP13 elimination half-life was also found to be different between the groups (<0.01). The bioavailability of PP13 following subcutaneous administration was found to be 57%.

Conclusion: This study shows that the concentration of total PP13 released into the maternal circulation during pregnancy might be much higher than previously estimated.
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http://dx.doi.org/10.2147/DDDT.S167926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037268PMC
January 2019

The Critical Role of Abnormal Trophoblast Development in the Etiology of Preeclampsia.

Curr Pharm Biotechnol 2018 ;19(10):771-780

Department of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.

Background: The pregnancy pathology preeclampsia is still among the leading causes of maternal and perinatal morbidity and mortality. At the same time, its etiology is far from being identified and remains obscure in a number of facets. A number of hypotheses have been developed to explain the altered interplay between placenta and mother leading to the clinical symptoms of preeclampsia. However, none of them offers the opportunity to explain the variability of cases with late-onset versus early-onset, mild versus severe and with or without additional fetal growth restriction.

Conclusion: This paper identifies the weaknesses of the most important current hypothesis and at the same time offers a set of new elucidations including maternal susceptibility, and villous/extravillous trophoblast differentiation to explain the development of preeclampsia. Such elucidations allow following new scientific routes and pathways to untangle the etiology of preeclampsia.
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http://dx.doi.org/10.2174/1389201019666180427110547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463401PMC
February 2019

Trophoblast retrieval and isolation from the cervix: origins of cervical trophoblasts and their potential value for risk assessment of ongoing pregnancies.

Hum Reprod Update 2018 07;24(4):484-496

Department of Obstetrics and Gynecology, Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.

Background: Early during human development, the trophoblast lineage differentiates to commence placentation. Where the placenta contacts the uterine decidua, extravillous trophoblast (EVT) cells differentiate and invade maternal tissues. EVT cells, identified by expression of HLA-G, invade into uterine blood vessels (endovascular EVT), as well as glands (endoglandular EVT), and open such luminal structures towards the intervillous space of the placenta. Endoglandular invasion diverts the contents of uterine glands to the intervillous space, while glands near the margin of the placenta that also contain endoglandular EVT cells open into the reproductive tract. Cells of the trophoblast lineage have thus been recovered from the uterine cavity and endocervical canal. An emerging non-invasive technology [trophoblast retrieval and isolation from the cervix (TRIC)] isolates and examines EVT cells residing in the cervix to explore their origin, biology and relationship to pregnancy and fetal status.

Objective And Rationale: This review explores the origins and possible uses of trophoblast cells obtained during ongoing pregnancies (weeks 5-20) by TRIC. We hypothesize that endoglandular EVT cells at the margins of the expanding placenta enter the uterine cavity and are carried together with uterine secretion products to the cervix where they can be retrieved from a Papanicolaou (Pap) smear. The advantages of TRIC for investigation of human placentation and prenatal testing will be considered. Evidence from the literature, and from archived in utero placental histological sections, is presented to support these hypotheses.

Search Methods: We used 52 out of 80 publications that appeared between 1966 and 2017 and were found by searching the PubMed and Google Scholar databases. The studies described trophoblast invasion of uterine vessels and glands, as well as trophoblast cells residing in the reproductive tract. This was supplemented with literature on human placental health and disease.

Outcomes: The literature describes a variety of invasive routes taken by EVT cells at the fetal-maternal interface that could displace them into the reproductive tract. Since the 1970s, investigators have attempted to recover trophoblast cells from the uterus or cervix for prenatal diagnostics. Trophoblast cells from Pap smears obtained at 5-20 weeks of gestation have been purified (>95% β-hCG positive) by immunomagnetic isolation with nanoparticles linked to anti-HLA-G (TRIC). The isolated cells contain the fetal genome, and have an EVT-like expression profile. Similar EVT-like cells appear in the lumen of uterine glands and can be observed entering the uterine cavity along the margins of the placenta, suggesting that they are the primary source of cervical trophoblast cells. Cells isolated by TRIC can be used to accurately genotype the embryo/fetus by targeted next-generation sequencing. Biomarker protein expression quantified in cervical trophoblast cells after TRIC correlates with subsequent pregnancy loss, pre-eclampsia and fetal growth restriction. A key remaining question is the degree to which EVT cells in the cervix might differ from those in the basal plate and placental bed.

Wider Implications: TRIC could one day provide a method of risk assessment for maternal and fetal disease, and reveal molecular pathways disrupted during the first trimester in EVT cells associated with placental maldevelopment. As perinatal interventions emerge for pregnancy disorders and inherited congenital disorders, TRIC could provide a key diagnostic tool for personalized precision medicine in obstetrics.
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http://dx.doi.org/10.1093/humupd/dmy008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016716PMC
July 2018

Correction to: Expression of matrix metalloproteinase 12 is highly specific for non-proliferating invasive trophoblasts in the first trimester and temporally regulated by oxygen-dependent mechanisms including HIF-1A.

Histochem Cell Biol 2018 01;149(1):43

Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.

In the original publication, the contribution of Dr. Christian Eyth as equal first author was not indicated. This has been corrected confirming that U. Hidden and C. Eyth contributed equally to this work.
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http://dx.doi.org/10.1007/s00418-017-1626-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828265PMC
January 2018

The trophoblast survival capacity in preeclampsia.

PLoS One 2017 6;12(11):e0186909. Epub 2017 Nov 6.

Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.

Background: Preeclampsia has become the world's major maternal health problem putting a huge burden on mothers, newborns and also on the health systems. The pathogenesis of preeclampsia seems to include events in very early pregnancy affecting differentiation of placental villous trophoblast. The arising changes of the cell death spectrum from apoptosis via increased autophagy and aponecrosis to necrosis in turn induce systemic inflammation of the mother.

Methods: Placental tissue samples and maternal serum samples from 40 pregnant women were collected from normal pregnancy, IUGR, early-onset and late-onset preeclampsia. Immunohistochemistry for LC3B and Beclin-1 was quantified using systematic random sampling techniques. Serum levels of LDH and other markers were assessed in serum.

Results: Expression of the autophagy markers LC3B and Beclin-1 was significantly different between groups as was the LC3B/Beclin-1 ratio. Early-onset preeclampsia and IUGR had the highest autophagy protein expression levels, while normal pregnancy and late-onset preeclampsia had the highest LC3B/Beclin-1 ratio. Early-onset preeclampsia had the highest negative correlation with free LDH as cell defect marker.

Conclusions: Autophagy plays a critical role in the cell death spectrum and cellular survival capacity of villous trophoblast. Alterations in autophagic protein expression are involved in pathological pregnancies such as preeclampsia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186909PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673174PMC
November 2017

Personalized Therapy Against Preeclampsia by Replenishing Placental Protein 13 (PP13) Targeted to Patients With Impaired PP13 Molecule or Function.

Comput Struct Biotechnol J 2017 22;15:433-446. Epub 2017 Sep 22.

Institute of Cell Biology, Histology and Embryology & Biobank Graz, Medical University of Graz, Graz, Austria.

Hypertensive disorders affect about one third of all people aged 20 and above, and are treated with anti-hypertensive drugs. Preeclampsia (PE) is one form of such disorders that only develops during pregnancy. It affects ten million pregnant women globally and additionally causes fetal loss and major newborn disabilities. The syndrome's origin is multifactorial, and anti-hypertensive drugs are ineffective in treating it. Biomarkers are helpful for predict its development. Generic drugs, such as low dose aspirin, were proven effective in preventing preterm PE. However, it does not cure the majority of cases and many studies are underway for fighting PE with extended use of additional generic drugs, or through new drug development programs. This review focuses on placental protein 13 (PP13). This protein is only expressed in the placenta. Impaired PP13 DNA structure and/or its reduced mRNA expression leads to lower blood PP13 level that predict a higher risk of developing PE. Two polymorphic PP13 variants have been identified: (1) The promoter PP13 variant with an "A/A" genotype in the -98 position (versus "A/C" or "C/C"). Having the "A/A" genotype is coupled to lower PP13 expression, mainly during placental syncytiotrophoblast differentiation and, if associated with obesity and history of previous preeclampsia, it accurately predicts higher risk for developing the disorder. (2) A thymidine deletion at position 221 causes a frame shift in the open reading frame, and the formation of an early stop codon resulting in the formation of DelT, a truncated variant of PP13. In pregnant rodents, both short- and long- term replenishment of PP13 causes reversible hypotension and vasodilation of uterine vessels. Long-term exposure is also accompanied by the development of larger placentas and newborns. Also, only w/t PP13 is capable of inducing leukocyte apoptosis, providing maternal immune tolerance to pregnancy. Based on published data, we propose a targeted PP13 therapy to fight PE, and consider the design and conduct of animal studies to explore this hypothesis. Accordingly, a new targeted therapy can be implemented in humans combining prediction and prevention.
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http://dx.doi.org/10.1016/j.csbj.2017.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633742PMC
September 2017

Expression of matrix metalloproteinase 12 is highly specific for non-proliferating invasive trophoblasts in the first trimester and temporally regulated by oxygen-dependent mechanisms including HIF-1A.

Histochem Cell Biol 2018 Jan 9;149(1):31-42. Epub 2017 Oct 9.

Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.

During first trimester pregnancy, trophoblast cells invade from the placenta into the maternal decidua where they anchor the placenta and remodel luminal structures like spiral arteries. This process depends on proteases secreted by invading trophoblasts, which degrade extracellular matrix (ECM). We here aimed to identify proteases particularly important for trophoblast invasion. We generated a list of proteases capable of degrading decidual ECM and trophoblast integrins using MEROPS database and compared expression of these proteases between primary trophoblasts isolated from first trimester placenta (FT, n = 3), representing an invasive phenotype, vs trophoblasts isolated from term pregnancy (TT, n = 3), representing a non-invasive trophoblast phenotype. Matrix metalloproteinase 12 (MMP12) revealed highest expression levels in FT, with absent expression in TT. In situ hybridisation and immunofluorescence localised MMP12 specifically to extravillous trophoblasts (evCT) whilst Ki67 co-staining revealed that proliferating trophoblasts of the cell columns were almost negative for MMP12. Quantification revealed a decline in MMP12 positive evCT at the end of first trimester, when oxygen levels start rising. MMP12 promoter analysis identified potential binding sites for hypoxia-inducible factor (HIF-1) and other oxygen-sensitive transcription factors. Moreover, MMP12 protein was increased by low oxygen in FT in vitro and by addition of a HIF-1α activator. Collectively, MMP12 is a highly expressed protease specific for invasive evCT during the first trimester. MMP12 down regulation by increasing oxygen concentration enables temporal expression control of MMP12 and involves several mechanisms including HIF-1α. These findings suggest MMP12 involved in trophoblast invasion during the first trimester.
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http://dx.doi.org/10.1007/s00418-017-1608-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767211PMC
January 2018

Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker.

Circulation 2017 Nov 13;136(19):1824-1839. Epub 2017 Sep 13.

From Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (J.Z., M.S., F.H., N.H., D.N.M., Z.I.); Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité-Universitätsmedizin Berlin, Germany (J.Z., F.H., L.P., N.H., M.G., H.S., F.C.L., D.N.M., R.D.); Berlin Institute of Health, Germany (J.Z., F.H., L.P., N.H., M.G., F.C.L., D.N.M., R.D., Z.I.); Department of Obstetrics and Department of Gynecology, Charité-Universitätsmedizin Berlin, Germany (M.G.); German Centre for Cardiovascular Research, partner site Berlin, Germany (N.H., D.N.M.); Centre for Trophoblast Research, University of Cambridge, UK (H.W.Y.); Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Austria (B.H.); Molecular and Clinical Sciences Research Institute, St George's University of London, UK (J.E.C., G.W.); Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway (G.M.J., A.C.S.); University of Oslo, Norway (G.M.J., A.C.S.); Évolution des Régulations Endocriniennes, Muséum Nationale d'Histoire Naturelle, Paris, France (G.L.); HELIOS-Klinikum, Berlin, Germany (A.I., R.D.); Cologne Center for Genomics, University of Cologne, Germany (H.S.); and Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, UK (L.D.H.).

Background: Preeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in preeclampsia. Our study aims to investigate whether disturbed imprinting contributes to preeclampsia.

Methods: We first aimed to confirm that preeclampsia is a disease of the placenta by generating and analyzing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from healthy controls and patients with preeclampsia. Next, we identified differentially expressed genes in preeclamptic placentas and intersected them with the list of human imprinted genes. We used bioinformatics/statistical analyses to confirm association between imprinting and preeclampsia and to predict biological processes affected in preeclampsia. Validation included epigenetic and cellular assays. In terms of human specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque, and mouse preimplantation embryogenesis.

Results: We found disturbed placental imprinting in preeclampsia and revealed potential candidates, including and , with poorly explored imprinted status and no prior association with preeclampsia. As a result of loss of imprinting, was upregulated in 69% of preeclamptic placentas. Levels of correlated with classic preeclampsia markers. DLX5 is expressed in human but not in murine trophoblast. The DLX5 phenotype resulted in reduced proliferation, increased metabolism, and endoplasmic reticulum stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of preeclamptic placentas. Pan-mammalian comparative analysis identified as part of the human-specific regulatory network of trophoblast differentiation.

Conclusions: Our analysis provides evidence of a true association among disturbed imprinting, gene expression, and preeclampsia. As a result of disturbed imprinting, the upregulated affects trophoblast proliferation. Our in vitro model might fill a vital niche in preeclampsia research. Human-specific regulatory circuitry of might help explain certain aspects of preeclampsia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671803PMC
November 2017

Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age.

Fetal Diagn Ther 2018 21;43(4):250-265. Epub 2017 Jul 21.

Hy Laboratories, Rehovot, Israel.

Background: LGALS13 (placental protein 13 [PP13]) promoter DNA polymorphisms was evaluated in predicting preeclampsia (PE), given PP13's effects on hypotension, angiogenesis, and immune tolerance.

Methods: First-trimester plasma samples (49 term and 18 intermediate) of PE cases matched with 196 controls were collected from King's College Hospital, London, repository. Cell-free DNA was extracted and the LGALS13 exons were sequenced after PCR amplification. Expression of LGALS13 promoter reporter constructs was determined in BeWo trophoblast-like cells with luciferase assays. Adjusted odds ratio (OR) was calculated for the A/A genotype combined with maternal risk factors.

Results: The A/A, A/C, and C/C genotypes in the -98 promoter position were in Hardy-Weinberg equilibrium in the control but not in the PE group (p < 0.036). The dominant A/A genotype had higher frequency in the PE group (p < 0.001). The A/C and C/C genotypes protected from PE (p < 0.032). The ORs to develop term and all PE, calculated for the A/A genotype, previous PE, body mass index (BMI) >35, black ethnicity, and maternal age >40 were 15.6 and 11.0, respectively (p < 0.001). In luciferase assays, the "-98A" promoter variant had lower expression than the "-98C" variant in non-differentiated (-13%, p = 0.04) and differentiated (-26%, p < 0.001) BeWo cells. Forskolin-induced differentiation led to a larger expression increase in the "-98C" variant than in the "-98A" variant (4.55-fold vs. 3.85-fold, p < 0.001).

Conclusion: Lower LGALS13 (PP13) expression with the "A" nucleotide in the -98 promoter region position (compared to "C") and high OR calculated for the A/A genotype in the -98A/C promoter region position, history of previous PE, BMI >35, advanced maternal age >40, and black ethnicity could serve to aid in PE prediction in the first trimester.
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http://dx.doi.org/10.1159/000477933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882584PMC
October 2018

A comparative study of five physiological key parameters between four different human trophoblast-derived cell lines.

Sci Rep 2017 07 19;7(1):5892. Epub 2017 Jul 19.

Vienna University of Technology, Faculty of Technical Chemistry, Institute of Applied Synthetic Chemistry & Institute of Chemical Technologies and Analytics, Getreidemarkt 9, 1060, Vienna, Austria.

The human placenta plays a crucial role as the interface between mother and fetus. It represents a unique tissue that undergoes morphological as well as functional changes on the cellular and tissue level throughout pregnancy. To better understand how the placenta works, a variety of techniques has been developed to re-create this complex physiological barrier in vitro. However, due to the low availability of freshly isolated primary cells, choriocarcinoma cell lines remain the usual suspects as in vitro models for placental research. Here, we present a comparative study on the functional aspects of the choriocarcinoma cell lines BeWo, JAR and Jeg-3, as well as the first trimester trophoblast cell line ACH-3P as placental in vitro barrier models for endocrine and transport studies. Functional assays including tight junction immunostaining, sodium fluorescein retardation, trans epithelial resistance, glucose transport, hormone secretion as well as size-dependent polystyrene nanoparticle transport were performed using the four cell types to evaluate key functional parameters of each cell line to act a relevant in vitro placental barrier model.
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http://dx.doi.org/10.1038/s41598-017-06364-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517571PMC
July 2017

Placental expression of sFlt-1 and PlGF in early preeclampsia vs. early IUGR vs. age-matched healthy pregnancies.

Hypertens Pregnancy 2017 May 10;36(2):151-160. Epub 2017 Feb 10.

a Department of Obstetrics , Charité University Medicine , Berlin , Germany.

Objective: To investigate whether differences between early preeclampsia and early fetal growth restriction can be explained by differential placental expression patterns of sFlt-1, Flt-1, and PlGF.

Methods: Placental tissues and maternal blood samples from six cases of preeclampsia, seven IUGR, and six age-matched controls were studied for mRNA and protein levels as well as protein localization and expression intensity.

Results: Neither placental PlGF mRNA and protein expression nor placental villous trophoblast expression intensity of PlGF was altered by placental dysfunction.

Conclusion: High sFlt-1 concentrations may account for diminished maternal serum PlGF levels.
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http://dx.doi.org/10.1080/10641955.2016.1273363DOI Listing
May 2017

Placental protein 13 (PP13)-induced vasodilation of resistance arteries from pregnant and nonpregnant rats occurs via endothelial-signaling pathways.

Hypertens Pregnancy 2017 May 19;36(2):186-195. Epub 2017 May 19.

b Department of Obstetrics , Gynecology and Reproductive Sciences, University of Vermont , Burlington , Vermont , USA.

Placental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects on isolated uterine arteries from nonpregnant and mid-pregnant rats. Vessels were isolated, cannulated, and pressurized to 50 mmHg within an arteriograph, preconstricted and exposed to increasing PP13 concentrations (10-10 M). PP13 elicited 38-50% arterial vasodilation with half-maximum response (EC) = 1 pM. The relaxation was mediated by activating the endothelial-signaling pathways of prostaglandin and nitric oxide (NO). Accordingly, these results encourage evaluation of PP13 as a possible therapy for gestational diseases characterized by insufficient uteroplacental blood flow and/or maternal hypertension.
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http://dx.doi.org/10.1080/10641955.2017.1295052DOI Listing
May 2017

Increased placental sFlt-1 but unchanged PlGF expression in late-onset preeclampsia.

Hypertens Pregnancy 2017 May 11;36(2):175-185. Epub 2017 May 11.

a Department of Obstetrics , Campus Virchow-Clinic, Charite´ University Medicine , Berlin , Germany.

Objective: To investigate whether differences between late-onset preeclampsia (PE) and intrauterine growth restriction (IUGR) can be explained by differential placental expression patters of sFlt-1, Flt-1, and placental growth factor (PlGF).

Methods: Placental tissues and maternal blood samples from seven patients with PE, five IUGR, and seven age-matched controls were studied for mRNA and protein levels as well as protein localization and expression intensity.

Results: Placental PlGF mRNA and protein expression were not altered by placental dysfunction while placental villous trophoblast expression intensity of PlGF was increased.

Conclusion: High sFlt-1 concentrations may account for diminished maternal serum PlGF levels.
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http://dx.doi.org/10.1080/10641955.2017.1291673DOI Listing
May 2017

Challenges and Driving Forces for Business Plans in Biobanking.

Biopreserv Biobank 2017 Apr 24;15(2):121-125. Epub 2017 Mar 24.

Biobank Graz, Medical University of Graz , Austria .

Background: Due to increased utilization of biospecimens for research and emergence of new technologies, the availability and quality of biospecimens and their collection are coming more and more into focus. However, the long-term economic situation of biobanks is still mostly unclear. Also, the common sustainable utilization of various international biobanks is challenging due to local differences in sample processing, law and ethics.

Aim: This article discusses possible strategies to achieve a sustainable utilization of biospecimens as part of the business plan of biobanks.

Methods: The following questions were addressed as part of a business plan: (1) How can a biobank build up and maintain an up-to-date infrastructure? (2) What kind of funding can support the sustainability of a biobank? (3) Is there an international solution for informed consents to enable sample and data sharing? (4) How can a biobank react during economically unstable periods? (5) Which kind of biobanking research is innovative? (6) What kind of education could be most needful for knowledge transfer in biobanking? (7) Does an expiration date for a biobank make sense according to the period of funding?

Conclusion: A strategy for optimal utilization begins with sharing of resources, infrastructure, and investments at the planning stage of a biobank, and continues to the transfer of knowledge and know-how by education. For clinical biobanks in particular, a long-term funding and cost recovery strategy is necessary for sustainable utilization.
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http://dx.doi.org/10.1089/bio.2017.0018DOI Listing
April 2017
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