Early onset preeclampsia in a model for human placental trophoblast.

Sheridan, Megan A

Yang, Ying

Jain, Ashish

Lyons, Alex S

Yang, Penghua

Brahmasani, Sambasiva R

Dai, Aihua

Tian, Yuchen

Ellersieck, Mark R

Tuteja, Geetu

Schust, Danny J

Schulz, Laura C

Ezashi, Toshihiko

Roberts, R Michael

2023-06-12T17:32:26Z

2023-06-12T17:32:26Z

2019-03

2023-06-12T17:32:23Z

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.

1816150116

0027-8424

1091-6490

https://hdl.handle.net/10161/27908

eng

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences of the United States of America

10.1073/pnas.1816150116

Trophoblasts

Placenta

Humans

Pre-Eclampsia

Oxygen

Membrane Transport Proteins

Gene Expression Profiling

Cell Adhesion

Cell Movement

Gene Expression Regulation

Oxidative Stress

Pregnancy

Female

Bone Morphogenetic Protein 4

Induced Pluripotent Stem Cells

Transcriptome

Gene Ontology

Early onset preeclampsia in a model for human placental trophoblast.

Journal article

Schust, Danny J|0000-0003-4561-7808

4336

4345

10

Duke

School of Medicine

Clinical Science Departments

Obstetrics and Gynecology

Obstetrics and Gynecology, Reproductive Endocrinology & Fertility

Published

116