Early onset preeclampsia in a model for human placental trophoblast

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% O2conditions, 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 O2response mechanisms and that EOPE is a syndrome, in which unbalanced expression of various combinations of genes affecting TB invasion provoke disease onset.

Two distinct trophectoderm lineage stem cells from human pluripotent stem cells

“…In contrast, hiPSC-derived 329 hTSCs and hTESCs, from hiPSCs generated using somatic tissues obtained at term, will enable 330 development of models of validated normal and pathological trophoblast development. Perti-331 nently, Sheridan et al (2019) have derived hiPSCs from umbilical cords of normal pregnancies 332 and those associated with early onset preeclampsia. Our results also gain particular significance 333 in the light of restrictions on research with fetal tissue (Du Toit, 2019).…”

Effect for Human Genomic Variation During the BMP4-Induced Conversion From Pluripotent Stem Cells to Trophoblast

“…The three cell lines and the matched BMP4 induced cell lines was obtained from the Roberts's laboratory, University of Missouri. For more details of these three pairs of cell lines see Sheridan et al (2019). MRucR iPSC was established from umbilical cords of babies born to mothers who experienced an early-onset form of preeclampsia during their pregnancies.…”

“…MRucR iPSC was established from umbilical cords of babies born to mothers who experienced an early-onset form of preeclampsia during their pregnancies. The BMP4-inducing experiment was performed as previously described (Sheridan et al, 2019). Briefly, the trophoblast stem cells were exposed to BMP4 in combination with signaling inhibitors of ACTIVIN-A (A83-01) and FGF2 (PD173074) (BAP treatment) (Sheridan et al, 2019).…”

“…In this study, we analyzed the genomic DNA sequences for three paired human ESCs and iPSC (H1, H9, and MRucR) (Sheridan et al, 2019). We demonstrated that some of the genomic variations can affect the differentiation by altering TFs' binding affinity.…”

Rewiring of gene expression in circulating white blood cells is associated with pregnancy outcome in heifers (Bos taurus)

“…The enrichment for specific biological processes of genes that formed new negative connections was a clear evidence of the biological relevance of these new connections. Notably, among genes annotated with proteolytic activity, ADAM19 39 , ASRGL1 40 , ATG4B 41 , DPEP2 42 , IMMP2L 43 , PSMB9 44 , SERPINE2 45 , UCHL3 46 , USP42 47 have been implicated in female infertility. A more drastic change in patterns of coexpression was observed with the inversion of gene connections (significant pairwise coexpression in one group with significant coexpression with opposite direction in another group).…”