Abnormal Oxidative Stress Responses in Fibroblasts from Preeclampsia Infants

Abstract

BackgroundSigns of severe oxidative stress are evident in term placentae of infants born to mothers with preeclampsia (PE), but it is unclear whether this is a cause or consequence of the disease. Here fibroblast lines were established from umbilical cords (UC) delivered by mothers who had experienced early onset PE and from controls with the goal of converting these primary cells to induced pluripotent stem cells and ultimately trophoblast. Contrary to expectations, the oxidative stress responses of these non-placental cells from PE infants were more severe than those from controls.Methods and FindingsThree features suggested that UC-derived fibroblasts from PE infants responded less well to oxidative stressors than controls: 1) While all UC provided outgrowths in 4% O2, success was significantly lower for PE cords in 20% O2; 2) PE lines established in 4% O2 proliferated more slowly than controls when switched to 20% O2; 3) PE lines were more susceptible to the pro-oxidants diethylmaleate and tert-butylhydroquinone than control lines, but, unlike controls, were not protected by glutathione. Transcriptome profiling revealed only a few genes differentially regulated between PE lines and controls in 4% O2 conditions. However, a more severely stressed phenotype than controls, particularly in the unfolded protein response, was evident when PE lines were switched suddenly to 20% O2, thus confirming the greater sensitivity of the PE fibroblasts to acute changes in oxidative stress.ConclusionsUC fibroblasts derived from PE infants are intrinsically less able to respond to acute oxidative stress than controls, and this phenotype is retained over many cell doublings. Whether the basis of this vulnerability is genetic or epigenetic and how it pertains to trophoblast development remains unclear, but this finding may provide a clue to the basis of the early onset, usually severe, form of PE.

Early onset preeclampsia in a model for human placental trophoblast

“…1 C , left). Together, these experiments suggest that the O 2 susceptibility of the primary fibroblast cultures, which were used as the progenitors of the iPSCs, might have been lost as a result of reprogramming ( 22 ). Finally, there was no indication that male (triangles) and female (circles) fibroblast or iPSC lines could be readily distinguished as assessed by PCA of global gene expression under either O 2 condition ( Fig.…”

“…These BAP-derived TBs are thought to represent highly invasive cells of the primitive placenta ( 20 , 21 ), and therefore provide an advantageous model to study EOPE. To capture potential genetic or epigenetic features that might characterize EOPE, fibroblast cells were cultured from explants from umbilical cords (UC) of babies born to mothers who had experienced EOPE during their pregnancies as well as homologous cells from UC of infants born to mothers following a normal pregnancy to act as controls (CTLs) ( 22 ). It was noted that establishing cultures under 20% O 2 conditions proved significantly more challenging from EOPE than CTL UC explants and that the cells were more susceptible to oxidative stress, suggesting that there were possibly genetic differences that distinguished the two ( 22 ).…”

Mode of conception does not appear to affect placental volume in the first trimester

“…It is suggested that aberrations, including alterations in oxidative stress, lead to abnormal placentation and failure of trophoblast invasion occurring in the first trimester which lead to adverse pregnancy outcomes. (36–38) The placenta serves a fundamental role in transferring oxygen and nutrition to the growing fetus and not surprisingly, placental size and shape at delivery, have been shown to strongly correlate with newborn birth weight. (39–41) Although we did not find differences in estimated placental volume or placental weight based on mode of conception, placental abnormalities leading to complications may occur at the molecular level in IVF conceptions that are not related to cytogenetic abnormalities, as cytogenetic abnormalities are not increased among these groups.…”

Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure

“…6I), reduced the amount of placental hormones released into the medium, and accentuated expression of HLA-G, suggesting that the colonies contained a higher proportion of extravillous trophoblast. Confirming these hypotheses will require additional experiments, but the ability to bias trophoblast differentiation toward either cell type might be of value in understanding the pathobiology of a disease like pre-eclampsia, where placental development appears to be abnormal (58).…”