Early onset preeclampsia in a model for human placental trophoblast

Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4336-4345. doi: 10.1073/pnas.1816150116. Epub 2019 Feb 20.

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.

MeSH terms

  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Adhesion
  • Cell Movement
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Ontology
  • Humans
  • Induced Pluripotent Stem Cells
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Oxidative Stress
  • Oxygen / pharmacology
  • Placenta / metabolism*
  • Pre-Eclampsia / metabolism*
  • Pregnancy
  • Transcriptome
  • Trophoblasts / metabolism*

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Membrane Transport Proteins
  • choline transporter-like protein 4, human
  • Oxygen