Identification of altered miRNAs and their targets in placenta accreta

Murrieta-Coxca, José Martín; Barth, Emanuel; Fuentes-Zacarías, Paulina; Gutiérrez-Samudio, Ruby N.; Groten, T; Gellhaus, Alexandra; Köninger, Angela; Marz, Manja; Markert, Udo R.; Morales-Prieto, Diana M.

doi:10.3389/fendo.2023.1021640

Cited by 10 publications

(15 citation statements)

References 107 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we only identified 16 differentially expressed genes between placenta accreta and increta regions, one of these was NF-κB2 which is a regulator of normal trophoblast invasion (21). NF-κB is expressed in syncytiotrophoblast and the stroma of placental villi, and increased protein expression of NF-κB has been described in PAS (22). ALX1, which has been linked to increased epithelial–mesenchymal transition (EMT) and invasion in malignancy (23), was also increased in placenta increta compared to accreta regions.…”

Section: Resultsmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Tissues were collected during cesarean sectio procedures from women in the first cohort (Table 1) with diagnoses of placenta cre (seven patients), placenta increta (six patients), and placenta percreta (four patients). [21,[34][35][36]. However, miRNA markers identified in the third trimester of pregnancy in studies conducted to ize the management tactics of pregnant women, preparing for qualifie at the time of delivery with the possibility of blood transfusion, it is screening of women in the first trimester of pregnancy for the conten of PAS in blood serum.…”

Section: Analysis Of Mirna Expression Patterns Using Deep Sequencing ...mentioning

confidence: 99%

“…In the initial stage of the study, deep seque ployed to obtain and compare the expression pr regions of the placenta and myometrium. Tissu procedures from women in the first cohort (T (seven patients), placenta increta (six patients), sion [32,33], miRNAs, acting as master regulators of the human genome at the transcriptional and post-transcriptional levels, were analyzed in various biological samples to associate their levels with PAS [21,[34][35][36]. However, miRNA markers for PAS have been identified in the third trimester of pregnancy in studies conducted to date.…”

Section: Analysis Of Mirna Expression Patterns Using Myometrial Tissu...mentioning

confidence: 99%

“…Tissues were collected during cesarean section procedures from women in the first cohort (Table 1) with diagnoses of placenta creta (seven patients), placenta increta (six patients), and placenta percreta (four patients). sion [32,33], miRNAs, acting as master regulators of the human genome at the transcri tional and post-transcriptional levels, were analyzed in various biological samples to a sociate their levels with PAS [21,[34][35][36]. However, miRNA markers for PAS have be identified in the third trimester of pregnancy in studies conducted to date.…”

Section: Analysis Of Mirna Expression Patterns Using Deep Sequencing ...mentioning

confidence: 99%

“…Due to the epigenetic regulation of trophoblast differentiation, migration, and invasion [32,33], miRNAs, acting as master regulators of the human genome at the tran-scriptional and post-transcriptional levels, were analyzed in various biological samples to associate their levels with PAS [21,[34][35][36]. However, miRNA markers for PAS have been identified in the third trimester of pregnancy in studies conducted to date.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Diagnostic Role of Cell-Free miRNAs in Identifying Placenta Accreta Spectrum during First-Trimester Screening

Timofeeva,

Fedorov,

Suhova

et al. 2024

IJMS

View full text Add to dashboard Cite

Placenta accreta spectrum (PAS) is a severe complication of pregnancy associated with excessive invasion of cytotrophoblast cells at the sites of the endometrial–myometrial interface and the myometrium itself in cases of adherent (creta) and invasive (increta and percreta) forms, respectively. This leads to a high risk of massive blood loss, maternal hysterectomy, and preterm birth. Despite advancements in ultrasound protocols and found associations of alpha-fetoprotein, PAPP-A, hCG, PLGF, sFlt-1, IL-8, and IL-33 peripheral blood levels with PAS, there is a high need for an additional non-invasive test to improve the diagnostic accuracy and to select the real PAS from the suspected ones in the first-trimester screening. miRNA signatures of placental tissue, myometrium, and blood plasma from women with PAS in the third trimester of pregnancy, as well as miRNA profiles in exosomes from the blood serum of women in the first trimester with physiologically progressing pregnancy, complicated by PAS or pre-eclampsia, were obtained using deep sequencing. Two logistic regression models were constructed, both featuring statistically significant parameters related to the levels of miR-26a-5p, miR-17-5p, and miR-101-3p, quantified by real-time PCR in native blood serum. These models demonstrated 100% sensitivity in detecting PAS during the first pregnancy screening. These miRNAs were identified as specific markers for PAS, showing significant differences in their blood serum levels during the first trimester in the PAS group compared to those in physiological pregnancies, early- or late-onset pre-eclampsia groups. Furthermore, these miRNAs exhibited differential expression in the PAS placenta and/or myometrium in the third trimester and, according to data from the literature, control angiogenesis. Significant correlations were found between extracellular hsa-miR-101-3p and nuchal translucency thickness, hsa-miR-17-5p and uterine artery pulsatility index, and hsa-miR-26a-5p and hsa-miR-17-5p with PLGF. The developed test system for early non-invasive PAS diagnosis based on the blood serum level of extracellular miR-26a-5p, miR-17-5p, and miR-101-3p can serve as an auxiliary method for first-trimester screening of pregnant women, subject to validation with independent test samples.

show abstract