Placental and trophoblastic in vitro models to study preventive and therapeutic agents for preeclampsia
Introduction
Placental insufficiency plays a crucial role in the development of preeclampsia and fetal growth restriction, pregnancy pathologies with still unknown etiologies [1]. Preeclampsia is one of the leading causes for maternal and neonatal mortality and morbidity. Therefore, major efforts are ongoing to identify markers for the early prediction of preeclampsia. Such markers will assist in developing appropriate management tools and preventive therapies to finally find agents to eliminate preeclampsia.
The last years have shown an enormous progress in the availability of predictive markers and the usefulness of their combination in either concurrent or contingent approaches [2]. This progress has prepared the ground to consider screening, and in fact screening for preeclampsia with different sonographic and biomarker assays is currently offered in a limited number of centers of excellence.
The development of preeclampsia prevention and management is lagging behind novel drug development for other multifactorial diseases. The use of animal models to study placental alterations in preeclampsia was considered dubious in view of the very different processes of placentation between human and other mammals. As a result, most candidate therapeutics were tested directly on human. However, due to ethical constrains, and often in conjunction with financial limitations, studies lack sufficient power or failed due to limitations of design in the absence of suitable model systems to better substantiate them. The benefit of a research approach based on in vitro models combined with the use of disease screening and diagnosis markers proved very effective in developing treatment of diabetes, hyper-cholesterol, or leukemia, to name a few.
In this paper we review two in vitro models in the context of evaluating drug candidates in preventing and treating preeclampsia using preeclampsia markers as monitoring tools to evaluate drug benefit. Such in vitro systems include placental villous explants and trophoblast derived choriocarcinoma cells, which are first tested on the effects of putative therapeutics and second on the effects of blood samples from healthy and preeclamptic women in combination with the putative therapeutics. The criteria of evaluating the performance of such systems include viability, proliferation and morphological criteria of tissues and cells as well as expression and release of disease-related screening and diagnostic biomarkers. The value of marker changes known to have a value in predicting preeclampsia in the presence of putative preventive and managing anti-preeclampsia agents is then reviewed.
Section snippets
In vitro models
To leverage the progress in biomarker development, in vitro models are required for the assessment of preventive means before such putative therapeutics can be incorporated in large scale clinical trials.
First line models are animal models. Indeed, a number of animal models have been developed to mimic preeclampsia. Most models make use of rodents such as rats and mice. However, these rodent models lack the profound invasion of trophoblast into the endometrium and myometrium as well as the
Conclusions
The last few years have seen an enormous progress in terms of marker development to predict and diagnose preeclampsia. On the other hand, the introduction of these effective markers into routine prediction of preeclampsia progresses very slowly due to the lack of effective therapeutics or other agents. The benefit of a research approach based on in vitro models combined with the use of disease screening and diagnosis markers proved very effective in developing treatment of diabetes,
Contributors
B.H. and H.M. supervised the experiments, participated in data analysis and jointly wrote the manuscript. K.O. and V.K. performed cell culture, cryoprotection and biochemical experiments, M.S. and Y.G. E.L. developed the procedure for placenta system processing, culturing and explant sampling, E.L. developed the methodology for cryopreservation and cryoprotectant selection, and R.G. obtained patient informed consent, built the patient information system, audited clinical outcome, collected
Role of funding source
This work was supported by a research grant of the European Union (FP6-grant # 037244, project title Pregenesys).
Conflict of interest
H.M. is CEO & director of Diagnostic Technologies Ltd (DTL), and has options for ordinary shares on the company accounting for 3.5% in the company shares on a fully diluted basis. M.S., V.K. and Y.G. are employees of DTL and their salary is paid from the grant sponsored by this research.
Acknowledgements
This work was supported by a research grant of the European Union (FP6-grant #037244, project title Pregenesys). K.O. was funded by the EU (FP6-Grant #037244) within the PhD program Molecular Medicine of the Medical University of Graz.
References (52)
- et al.
Prevention of preeclampsia and eclampsia
- et al.
Changes in endovascular trophoblast invasion and spiral artery remodelling at term in a transgenic preeclamptic rat model
Placenta
(2010) - et al.
Isolation of pure villous cytotrophoblast from term human placenta using immunomagnetic microspheres
J Immunol Methods
(1989) - et al.
Preparation and functional characterization of villous cytotrophoblasts free of syncytial fragments
Placenta
(2002) - et al.
Vitamins C and E inhibit apoptosis of cultured human term placenta trophoblast
Placenta
(2008) - et al.
Human placental explants in culture: approaches and assessments
Placenta
(2005) - et al.
Oxygen and the liberation of placental factors responsible for vascular compromise
Lab Invest
(2008) - et al.
Uric acid inhibits placental system A amino acid uptake
Placenta
(2009) - et al.
Longevity of cryogenically stored seeds
Cryobiology
(2004) - et al.
Cryopreservation and short-term storage of sturgeon sperm, a review
Aquaculture
(2004)
Livebirth after orthotopic transplantation of cryopreserved ovarian tissue
Lancet
Freeze-thawing intact human ovary with its vascular pedicle with a passive cooling device
Fertil Steril
Cell culture models of trophoblast II: trophoblast cell lines – a workshop report
Placenta
The paradox of caspase 8 in human villous trophoblast fusion
Placenta
Caspase 8 and human villous cytotrophoblast differentiation
Placenta
Syncytin-2 plays an important role in the fusion of human trophoblast cells
J Mol Biol
Quantifying the syncytialisation of human placental trophoblast BeWo cells grown in vitro
Biochim Biophys Acta
A two-colour fluorescence assay for the measurement of syncytial fusion between trophoblast derived cell lines
Placenta
Phosphatidylserine efflux and intercellular fusion in a BeWo model of human villous cytotrophoblast
Placenta
Expression of endogenous retrovirus ERV-3 induces differentiation in BeWo, a choriocarcinoma model of human placental trophoblast
Placenta
Effects of vitamins C and E, acetylsalicylic acid and heparin on fusion, beta-hCG and PP13 expression in BeWo cells
Placenta
Modulators of cyclic AMP metabolism induce syncytiotrophoblast formation in vitro
Exp Cell Res
Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions
FEBS Lett
GCMa regulates the syncytin-mediated trophoblastic fusion
J Biol Chem
Cytogenetic and DNA-fingerprint characterization of choriocarcinoma cell lines and a trophoblast/choriocarcinoma cell hybrid
Cancer Genet Cytogenet
Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial
Lancet
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2021, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :This represents a main limitation to the use primary trophoblast model in screening all the possible adverse effects of NPs on feto-maternal interface (Fig. 4) [94]. Furthermore, limited accessibility and short-time window viability problems limits the feasibility of using this model [94,95]. Choriocarcinoma-based trophoblast cell lines have been extensively utilized to mimic the placental barrier for screening NP toxicity, translocation and uptake (see Table 2) [42,95,101].
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Both authors have equally contributed to the study.