Trophoblast Apoptosis in Placentas from Pregnancies Complicated by Preeclampsia

Tomaš, Sandra Zekić; Prusac, Ivana Kuzmić; Roje, Damir; Tadin, Ivica

doi:10.1159/000320289

Cited by 72 publications

(45 citation statements)

References 44 publications

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“…These results suggested that EVTB in early preeclamptic placentas might have higher levels of cell death. This conclusion is in line with previous reports that trophoblastic apoptosis is increased in PE (52)(53)(54)(55)(56)(57)(58)(59). Despite the invasion insufficiency of EVTB in PE, the increased cell death in EVTB may also contribute to the up-regulation of the EVTB signatures in the maternal plasma of early preeclamptic patients.…”

Section: Deciphering Cellular Aberrations In Preeclamptic Placentas Fromsupporting

confidence: 92%

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Tsang

Vong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

265

267

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The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type-specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions. single-cell transcriptomics | cell-free RNA | noninvasive prenatal testing | placenta | preeclampsia

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Section: Deciphering Cellular Aberrations In Preeclamptic Placentas Fromsupporting

confidence: 92%

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Tsang

Vong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

265

267

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“…Increased apoptosis of villous trophoblast and reduced FasL expression have been reported to be involved in pathophysiological mechanisms of preeclampsia [19,20] . Inappropriate extravillous trophoblast apoptosis has been implicated in the failure of trophoblast to fully invade and modify the uterine environment, potentially leading to preeclampsia [21][22][23] .…”

Section: Discussionmentioning

confidence: 99%

Decreased Cyr61 under hypoxia induces extravillous trophoblasts apoptosis and preeclampsia

Chen

Liu

et al. 2011

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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During placental development, oxygen environment is not only critical for trophoblasts migration and invasion, but also fundamental for appropriate placental perfusion. Cysteine-rich 61 (Cyr61, CCN1) was expressed in the extravillous trophoblasts (EVTs) and decreased in preeclampsia. Its regulatory properties in human first-trimester extravillous trophoblast cell line (TEV-1 cells) upon a low oxygen tension were investigated. The present study examined functional changes involved in adaptation to hypoxia of the TEV-1 cells, using cobalt chloride (CoCl(2)) as hypoxic mimic. It was found that hypoxia inhibited growth of TEV-1 cells and induced the increase of cell apoptosis (P<0.05). The Cyr61 expression in human EVTs was transcriptionally induced by CoCl(2). Inappropriate EVTs apoptosis has been implicated in the failure of trophoblasts to fully invade and modify the uterine environment and Cyr61 down-regulation, potentially leading to preeclampsia.

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“…the very early stages of pregnancy. The morphological changes in placentas of preeclamptic women (insufficient trophoblast invasion with increased apoptosis and syncytial knot formation, poor remodeling of the uterine spiral arteries, local fibrin deposits) [1] are still mainly explained by the multistep theory, which describes the role of several pathomechanisms in the development of PE, e.g. endothelial cell dysfunction [2], systemic vasospasm, poor angiogenesis due to disorders in the network of angiogenic/antiangiogenic factors [3,4], placental hypoxia-reoxygenation injury by reactive oxygen species [5], increased placental expression level of Hsp27 [6], genetic susceptibility [7] and excessive maternal inflammation [8].…”

Section: Introductionmentioning

confidence: 99%

TNF-α G308A Gene Polymorphism Has an Impact on Renal Function, Microvascular Permeability, Organ Involvement and Severity of Preeclampsia

Žúbor

Dokus²,

Zigo³

et al. 2014

Gynecol Obstet Invest

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Background/Aims: Preeclampsia (PE) is a life-threatening complication of pregnancy that is associated with a high rate of maternal and perinatal morbidity and/or mortality worldwide. If untreated, it can progress to eclampsia, which can result in the death of the mother, the fetus or both. The etiology of PE is still uncertain; however, recently the role of the immune system has gained in importance. The role of tumor necrosis factor-α (TNF-α), a cytokine involved in inflammation processes, has been widely investigated in obstetric disorders. The aims of the present study were to investigate the effect of TNF-α gene G308A (rs1800629) polymorphism on disease risk, renal function, microvascular permeability, endothelial cell dysfunction and organ involvement in women with PE. Methods: Initially, 102 3rd-trimester pregnant women (preeclamptic cases and healthy controls) with singleton pregnancy were invited for participation, of which 76 were genotyped for TNF-α G308A polymorphism and evaluated for plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), fibronectin and TNF-α, which were tested for correlations with the profile of PE. The odds ratio (OR) and 95% confidence intervals obtained from unconditional logistic regression were used to test the association between the TNF-α polymorphism and PE risk. For continuous variables, we applied Student's t test and, for categorical variables, the Pearson χ² or Fisher's exact test. The two-way ANOVA test with Bonferroni correction was used in multivariate analyses. Results: The A allele was more frequent in cases than controls (22.4 vs. 13.2%), which increased disease risk (OR = 2.73). Maternal serum levels of TNF-α, sVCAM-1 and fibronectin were significantly increased in cases (855.8 ± 385.1 pg/ml, 1,243 ± 671 ng/ml, 0.308 ± 0.231 g/l, respectively) compared to controls (301.1 ± 156.1 pg/ml, 651 ± 250 ng/ml, 0.218 ± 0.101 g/l, respectively; p < 0.0001, p < 0.0001 and p = 0.031, respectively), and these levels showed an increasing trend with the mutant allele genotype. Moderate and severe proteinuria was higher in rs1800629 allele A subjects compared to G/G carriers (53.8 vs. 14.3% (p < 0.05) and 13.0 vs. 4.7% (p < 0.01), respectively). The adverse effect of rs1800629 allele A on renal function was confirmed by increased plasma creatine levels, urinary protein excretion and lower tubular resorption rate in preeclamptic patients. Moreover, rs1800629 allele A preeclamptic carriers showed higher serum levels of fibronectin and sVCAM-1 compared to G/G homozygotes. Conclusion: This study reveals a possible association between clinical and laboratory manifestations of PE and the TNF-α gene G308A (rs1800629) polymorphism.

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Trophoblast Apoptosis in Placentas from Pregnancies Complicated by Preeclampsia

Cited by 72 publications

References 44 publications

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Decreased Cyr61 under hypoxia induces extravillous trophoblasts apoptosis and preeclampsia

TNF-α G308A Gene Polymorphism Has an Impact on Renal Function, Microvascular Permeability, Organ Involvement and Severity of Preeclampsia

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