Placenta‐mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes

Bouvier, Sylvie; Mousty, E.; Fortier, Mathieu; Dematteï, Christophe; Mercier, Éric; Cochery-Nouvellon, Éva; Chéa, Mathias; Grosjean, Frédéric; Letouzey, V.; Gris, Jean‐Christophe

doi:10.1111/jth.15105

Cited by 9 publications

(9 citation statements)

References 38 publications

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“…Several studies, including our data, 4 have shown that plasma nucleosomes and cell-free DNA (cfDNA) increased during pregnancy, and that their levels were even higher in women with PMPCs, particularly in PE. 5,6 Nucleosomes are key components of neutrophil extracellular traps (NETs) and are released by neutrophil activation, a process called NETosis.…”

Section: Introductionsupporting

confidence: 53%

“…It was a pilot monocentric study with a small sample size, mainly of women developing PE or IUGR, based on our recruitment capacities in the main "Grosspath" study (clinicaltrials.gov identifier: NCT 01736826). 4 Placenta-mediated complications often present as a clinical emergency with women under stress, making inclusion of these patients complicated. In addition, due to the strong commitment of women in the normal pregnancy longitudinal follow-up group, with a significant number of visits and blood tests required, it was difficult to increase inclusion numbers.…”

Section: Discussionmentioning

confidence: 99%

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NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

et al. 2021

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NETosis is an innate immune response occurring after infection or inflammation: activated neutrophils expel decondensed DNA in complex with histones into the extracellular environment in a controlled manner. It activates coagulation and fuels the risk of thrombosis. Human pregnancy is associated with a mild proinflammatory state characterized by circulatory neutrophil activation which is further increased in complicated pregnancies, placenta-mediated complications being associated with an increased thrombotic risk. This aberrant activation leads to an increased release of nucleosomes in the blood flow. The aim of our study was to initially quantify nucleosome-bound histones in normal pregnancy and in placenta-mediated complication counterpart. We analyzed the role of histones on extravillous trophoblast function. Circulating nucleosome-bound histones H3 (Nu.QH3.1, Nu.QH3PanCit, Nu.QH3K27me3) and H4 (Nu.QH4K16Ac) were increased in complicated pregnancies. In vitro using the extravillous cell line HTR-8/SVNeo, we observed that free recombinant H2B, H3, and H4 inhibited migration in wound healing assay, but only H3 also blocked invasion in Matrigel-coated Transwell experiments. H3 and H4 also induced apoptosis, whereas H2B did not. Finally, the negative effects of H3 on invasion and apoptosis could be restored with enoxaparin, a low-molecular-weight heparin (LMWH), but not with aspirin. Different circulating nucleosome-bound histones are increased in complicated pregnancy and this would affect migration, invasion, and induce apoptosis of extravillous trophoblasts. Histones might be part of the link between the risk of thrombosis and pregnancy complications, with an effect of LMWH on both.

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Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

et al. 2021

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“…49 For example, in preeclampsia, incomplete endovascular trophoblast invasion with the reduced remodeling of uterine arteries leads to placental hypoperfusion and cytokine production, and increased nucleosome and cell-free DNA in plasma activate coagulation. 50 51 Different from other thrombotic DIC, the clinical characteristics of non–bleeding-caused obstetrical DIC are often organ dysfunction associated with bleeding. 52 The consumption of coagulation factors following activated coagulation, especially the depletion of fibrinogen, is the crucial point in the development of impaired hemostasis.…”

Section: Thrombosis-type Disseminated Intravascular Coagulationmentioning

confidence: 99%

Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations

Iba

Levi

Thachil

et al. 2022

Semin Thromb Hemost

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Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no “one-size-fits-all criteria.” Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.

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“… 35 , 36 The underlying pathologies responsible for such quantitative changes has not been fully elucidated but has been suspected to be related to increased placental cell death or apoptosis. 35 , 37 , 38 Circulating fetal DNA levels may therefore be reflective of placental health. Because massively parallel sequencing‐based methods mainly report DNA quantities as a fraction, researchers also studied if aberrant fetal DNA fractions were associated with pregnancy‐related or maternal conditions.…”

Section: Quantities and Abundancementioning

confidence: 99%

Cell‐free fetal DNA coming in all sizes and shapes

Chiu

2021

Prenatal Diagnosis

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Cell-free fetal DNA analysis has an established role in prenatal assessments. It serves as a source of fetal genetic material that is accessible non-invasively from maternal blood. Through the years, evidence has accumulated to show that cell-free fetal DNA molecules are derived from placental tissues, are mainly of short DNA fragments and have rapid post-delivery clearance profiles. But questions regarding how they come to being short molecules from placental cells and in which physical forms do they exist remained largely unanswered until recently. We now know that the distributions of ending sites of cell-free DNA molecules are non-random across the genome and bear correlations with the chromatin structures of cells from which they have originated. Such an insight offers ways to deduce the tissue-of-origin of these molecules. Besides, the physical nature and sequence characteristics of the ends of each cell-free DNA molecule provide tell-tale signs of how the DNA fragmentation processes are orchestrated by nuclease enzymes. These realizations offered opportunities to develop methods for enriching cell-free fetal DNA to facilitate non-invasive prenatal diagnostics. Here we aimed to collate what is known about the biological and physical characteristics of cell-free fetal DNA into one article and explain the implications of these observations. Key points What's already known about this topic?� Cell-free fetal DNA originates from placental tissues and circulates in maternal plasma as a minor population in the form of short fragments which disappears from maternal circulation rapidly after delivery. What does this study add?� Cell-free DNA studies at the per molecule per nucleotide level documented the detailed genomic distributions, fragment end characteristics and physical forms of cell-free DNA unveiling the fine feature differences between maternal and fetal DNA as well as their intricate relationships with the chromatin structure of the cells-of-origin. These studies have substantially bridged the knowledge gaps in the biology of cell-free fetal DNA and may provide insights on how to enhance prenatal tests based on their analyses.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Placenta‐mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes

Cited by 9 publications

References 38 publications

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations

Cell‐free fetal DNA coming in all sizes and shapes

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