PRG2 and AQPEP are misexpressed in fetal membranes in placenta previa and percreta<b>†</b>

Zhang, Elisa T.; Hannibal, Roberta L.; Rivera, K. M. Badillo; Song, Janet; McGowan, Kelly A.; Zhu, Xiaowei; Meinhardt, Gerold; Knöfler, Martin; Pollheimer, Jürgen; Urban, Alexander; Folkins, Ann K.; Lyell, Deirdre J.; Baker, Julie C.

doi:10.1093/biolre/ioab068

Cited by 7 publications

(5 citation statements)

References 117 publications

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“…Firstly, secretion of two uNK cytokines (CSF2 and XCL1) is increased after the activating KIR2DS1 binds to C2+HLA-C ligand; this genetic combination of mothers with KIR2DS1 and fetal C2+HLA-C is protective against pre-eclampsia and associated with larger babies 17,18,70 . Secondly, several of the gene signatures we have found altered by uNK cytokines have already been associated with these disorders in several studies: EBI3, MMP11, IL2RB, TGFBR2, ADAM12, PRG2, PAPPA and PAPPA2 [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86] (Table S1). Our study highlights the importance of now investigating the underlying mechanisms regulated by these genes that lead to different reproductive outcomes in humans, and provides candidate pathways with potential translational links to the clinic.…”

Section: Discussionmentioning

confidence: 86%

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Li¹,

Sharkey²,

Sheridan³

et al. 2023

Preprint

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Fetal growth and development during human pregnancy depends on delivery of adequate maternal oxygen and nutrients to the fetus via the placenta. In humans, the balanced invasion of fetal placental trophoblast cells into the maternal uterine lining, where they interact with uterine natural killer cells (uNK), is thought to be critical for a successful pregnancy but exactly how this influences reproductive outcomes remains undefined. Here, we used our trophoblast organoid model and primary tissue samples to determine how uNK affect placentation. By locating potential interaction axes between primary trophoblast cells and uNK using single cell transcriptomics, and in vitro modelling of these interactions in trophoblast organoids, we identify a uNK-derived cytokine signal that promotes trophoblast differentiation by enhancing epithelial-mesenchymal transition and increasing trophoblast cells at the late stage of the invasive pathway. Moreover, it affects transcriptional programs involved in increasing blood flow, placental access to nutrients, and dampening inflammatory and adaptive immune responses, as well as gene signatures associated with disorders of pregnancy such as pre-eclampsia. Our findings shed new light on how optimal immunological interactions between maternal uNK cells and fetal trophoblast enhance reproductive success.

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Section: Discussionmentioning

confidence: 86%

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Li¹,

Sharkey²,

Sheridan³

et al. 2023

Preprint

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“…PRG2 and IGF2 were the two most differentially expressed genes when comparing accreta to control and increta to control regions. PRG2 overexpression has been previously described in PAS (11, 24). PAPPA is a metalloproteinase which acts as a growth promoter in many tissues through release of IGF (25).…”

Section: Resultsmentioning

confidence: 99%

“…Single cell RNA-Seq studies in PAS identified upregulation of genes promoting invasion of EVTs, with one study describing a distinct excessive invasive cytotrophoblast cell types (LAMB4+ and KRT6A+) (10). Several genes involved in promoting EVT invasion, such as PRG2 and AQPEP, were abnormally expressed in the trophoblasts and fetal membranes of PAS cases (11). A further study found negative regulators of cell migration, such as podocin and apolipoprotein D, were downregulated in PAS, suggesting a pro-adhesive signature (12).…”

Section: Introductionmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

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In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4+, CD3+and CD8+T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITGβ1, including with fibronectin and ADAMS, emerging as central in increta. These ITGβ1 ligand interactions are involved in activation of epithelial–mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring. Overall, this study suggests the biological processes leading to deep trophoblast invasion in the myometrium in placenta increta are as a result of upregulation of transcription factors and subsequent genes and proteins which promote trophoblast invasion. This occurs in a locally immune suppressed environment, with increased ECM degradation suggesting these findings are secondary to iatrogenic uterine injury.Significance statementPlacenta Accreta Spectrum (PAS) is a rare pregnancy complication, where the placenta fails to separate from the womb resulting in severe bleeding, which is associated with significant maternal morbidity and mortality. As Caesarean section rates increase, the incidence of PAS is increasing. The underlying pathophysiology of PAS is poorly understood. Here, we apply a spatial multi-omic approach to explore the biologic changes at the maternal-fetal interface in severe PAS (placenta increta). Using spatial transcriptomics and proteomics, we identified genes and proteins that are dysregulated in severe PAS involving processes such as extracellular matrix degradation, local immune suppression and promotion of epithelial–mesenchymal transition. This study provides new insights into the biological changes and underlying pathophysiology leading to placenta increta.

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“…Increased PRG2 protein is seen in patients with placenta accreta spectrum and placenta previa, both of which are significant causes of pregnancy-associated morbidity. [54] IGFBP1 is also dysregulated due to pre-pregnancy obesity. Insulin-like growth factors and their binding proteins, the (IGFBPs) are expressed in the placenta and regulate fetal growth.…”

Section: Discussionmentioning

confidence: 99%

Maternal obesity-related placental dysfunction: From peri-conception to late gestation

Amabebe

Ikumi

Pillay

et al. 2023

PRM

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Obesity is a global epidemic with alarmingly high prevalence rates worldwide. The increasing incidence of obesity among reproductive age women, which progresses to obesity in pregnancy is of particular concern. A successful pregnancy is dependent on the balanced interaction between maternal cardiometabolic function, genetic predisposition, and optimal placental development. Maternal obesity, both pre-pregnancy and gestational, has been associated with adverse outcomes including poor fetal development, stillbirth, preterm birth, and metabolic complications later in life. To gain a more comprehensive understanding of the mechanistic interplay of key mediators of obesity-associated placental dysfunction and adverse pregnancy outcomes, we conducted a review of 24 studies that investigated placental dysfunction and maternal obesity retrieved from MEDLINE, LILACS and EMBASE. The findings demonstrate that maternal obesity is a well-established risk factor for poor placental function. Pre-pregnancy obesity alters the placental transcriptome. Maternal obesity during gestation induces changes in placental morphology, dysregulated placental metabolism, inflammation and oxidative state, as well as endothelial dysfunction. There is also clear evidence that maternal obesity is associated with altered placental angiogenesis/vascularisation which increases the risk of early-onset preeclampsia. Studies show a link between maternal obesity and increased placental vascular disorders, placental weight, placental volume and birth weight. These obesity-related placental disorders are often associated with insulin resistance and gestational diabetes mellitus.

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PRG2 and AQPEP are misexpressed in fetal membranes in placenta previa and percreta†

Cited by 7 publications

References 117 publications

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Spatial proteomics and transcriptomics of placenta accreta spectrum

Maternal obesity-related placental dysfunction: From peri-conception to late gestation

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