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Proc Natl Acad Sci U S A. 2019 Feb 20. pii: 201816150. doi: 10.1073/pnas.1816150116. [Epub ahead of print]

Early onset preeclampsia in a model for human placental trophoblast.

Author information

1
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
2
Bond Life Sciences Center, University of Missouri, Columbia, MO 65211.
3
Department of Pathology, Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
4
Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
5
Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620.
6
Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011.
7
Bioinformatics and Computational Biology, Iowa State University, Ames, IA 50011.
8
Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Maryland, Baltimore, Baltimore, MD 21201.
9
Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India.
10
Agriculture Experiment Station, University of Missouri, Columbia, MO 65211.
11
Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO 65212.
12
Department of Biochemistry, University of Missouri, Columbia, MO 65211; robertsrm@missouri.edu.

Abstract

We describe a model for early onset preeclampsia (EOPE) that uses induced pluripotent stem cells (iPSCs) generated from umbilical cords of EOPE and control (CTL) pregnancies. These iPSCs were then converted to placental trophoblast (TB) representative of early pregnancy. Marker gene analysis indicated that both sets of cells differentiated at comparable rates. The cells were tested for parameters disturbed in EOPE, including invasive potential. Under 5% O2, CTL TB and EOPE TB lines did not differ, but, under hyperoxia (20% O2), invasiveness of EOPE TB was reduced. RNA sequencing analysis disclosed no consistent differences in expression of individual genes between EOPE TB and CTL TB under 20% O2, but, a weighted correlation network analysis revealed two gene modules (CTL4 and CTL9) that, in CTL TB, were significantly linked to extent of TB invasion. CTL9, which was positively correlated with 20% O2 (P = 0.02) and negatively correlated with invasion (P = 0.03), was enriched for gene ontology terms relating to cell adhesion and migration, angiogenesis, preeclampsia, and stress. Two EOPE TB modules, EOPE1 and EOPE2, also correlated positively and negatively, respectively, with 20% O2 conditions, but only weakly with invasion; they largely contained the same sets of genes present in modules CTL4 and CTL9. Our experiments suggest that, in EOPE, the initial step precipitating disease is a reduced capacity of placental TB to invade caused by a dysregulation of O2 response mechanisms and that EOPE is a syndrome, in which unbalanced expression of various combinations of genes affecting TB invasion provoke disease onset.

KEYWORDS:

bone morphogenetic protein-4; cell migration; induced pluripotent stem cells; oxidative stress; transcriptome

PMID:
30787190
DOI:
10.1073/pnas.1816150116
Free PMC Article

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