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Front Immunol. 2018 Aug 8;9:1661. doi: 10.3389/fimmu.2018.01661. eCollection 2018.

Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.

Author information

1
Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States.
2
Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States.
3
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States.
4
Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
5
Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary.
6
First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
7
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States.
8
Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States.
9
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States.
10
Department of Computer Science, College of Engineering, Wayne State University, Detroit, MI, United States.
11
Laboratory of Proteomics, Department of Physiology and Neurobiology, ELTE Eotvos Lorand University, Budapest, Hungary.
12
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard University, Boston, MA, United States.
13
Zymo Research Corporation, Irvine, CA, United States.
14
Department of Obstetrics and Gynaecology, University of Debrecen, Debrecen, Hungary.
15
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
16
Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary.
17
Department of Morphology and Physiology, Semmelweis University, Budapest, Hungary.
18
TeleMarpe Ltd, Tel Aviv, Israel.
19
Department of Clinical and Translational Science, Wayne State University, Detroit, MI, United States.
20
Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States.
21
Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
22
Department of Obstetrics and Gynecology, Soroka University Medical Center School of Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
23
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
24
Department of Pathology, Wayne State University School of Medicine, Detroit, MI, United States.
25
Department of Pathology, Asan Medical Center, University of Ulsan, Seoul, South Korea.

Abstract

Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.

KEYWORDS:

inflammation; ischemia; liquid biopsy; omics; placenta; pregnancy; systems biology; trophoblast invasion

PMID:
30135684
PMCID:
PMC6092567
DOI:
10.3389/fimmu.2018.01661
[Indexed for MEDLINE]
Free PMC Article

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