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Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia
Yan Zhou, … , Michael T. McMaster, Susan J. Fisher
Yan Zhou, … , Michael T. McMaster, Susan J. Fisher
Published June 24, 2013
Citation Information: J Clin Invest. 2013;123(7):2862-2872. https://doi.org/10.1172/JCI66966.
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Research Article

Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia

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Abstract

During human pregnancy, a subset of placental cytotrophoblasts (CTBs) differentiates into cells that aggressively invade the uterus and its vasculature, anchoring the progeny and rerouting maternal blood to the placenta. In preeclampsia (PE), CTB invasion is limited, reducing placental perfusion and/or creating intermittent flow. This syndrome, affecting 4%–8% of pregnancies, entails maternal vascular alterations (e.g., high blood pressure, proteinuria, and edema) and, in some patients, fetal growth restriction. The only cure is removal of the faulty placenta, i.e., delivery. Previously, we showed that defective CTB differentiation contributes to the placental component of PE, but the causes were unknown. Here, we cultured CTBs isolated from PE and control placentas for 48 hours, enabling differentiation and invasion. In various severe forms of PE, transcriptomics revealed common aberrations in CTB gene expression immediately after isolation, including upregulation of SEMA3B, which resolved in culture. The addition of SEMA3B to normal CTBs inhibited invasion and recreated aspects of the PE phenotype. Additionally, SEMA3B downregulated VEGF signaling through the PI3K/AKT and GSK3 pathways, effects that were observed in PE CTBs. We propose that, in severe PE, the in vivo environment dysregulates CTB gene expression; the autocrine actions of the upregulated molecules (including SEMA3B) impair CTB differentiation, invasion and signaling; and patient-specific factors determine the signs.

Authors

Yan Zhou, Matthew J. Gormley, Nathan M. Hunkapiller, Mirhan Kapidzic, Yana Stolyarov, Victoria Feng, Masakazu Nishida, Penelope M. Drake, Katherine Bianco, Fei Wang, Michael T. McMaster, Susan J. Fisher

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Figure 1

sPE-associated aberrations in CTB gene expression returned to control values after 48 hours of culture.

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sPE-associated aberrations in CTB gene expression returned to control va...
RNA was analyzed immediately after the cells were isolated (0 hour) and after 12, 24, and 48 hours in culture. The relative gene expression levels for CTBs isolated from placentas of patients who delivered due to nPTL (n = 5) or sPE (n = 5) are shown as a heat map, ranging from high (red) to low (blue). The sPE CTBs were from the following cases (tiled from left to right): (a) HELLP syndrome and IUGR; (b) sPE; (c) sPE and IUGR; (d) superimposed sPE; and (e) HELLP syndrome. One sample of nPTL CTBs collected at 48 hours was omitted for technical reasons. The fold changes for each time point (sPE vs. nPTL) are shown on the right. ns, no significant difference (LIMMA); t, no significant difference in expression (sPE vs. nPTL) by 48 hours (maSigPro).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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