Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium

Afshar, Yalda; Yin, Ophelia; Jeong, Anhyo; Martinez, Guadalupe; Kim, Jina; Ma, Feiyang; Jang, Christine; Tabatabaei, Sarah; You, Sungyong; Tseng, Hsian-Rong; Zhu, Yazhen; Krakow, Deborah

doi:10.1016/j.ajog.2023.10.001

Cited by 8 publications

(8 citation statements)

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“…Furthermore, HLA-C is expressed on trophoblast cells in the Beta-2-microglobulin (B2M) form, and is the only HLA on EVT cells which can present paternal antigens and therefore plays an important role in preventing fetal rejection by the maternal immune system (36). We found B2M was increased in PAS regions in our study (see below), similar to previous studies (8, 24). These findings from the spatial transcriptomic data suggest the differentially expressed genes and their associated pathways found to be significant in placenta increta regions play a role in normal placental invasion in the setting of a scarred myometrium and an immunosuppressive environment.…”

Section: Resultssupporting

confidence: 93%

“…Inhibitors of apoptosis, such as BCL-2, BCLXL and fibronectin (61–63) were upregulated in regions of placenta increta (Figure 5c,d) consistent with previous studies (24, 64). BCL-2 is an important regulator of trophoblast apoptosis in normal pregnancy (65).…”

Section: Resultssupporting

confidence: 91%

“…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%

“…Following iatrogenic injury, the myometrium fails to fully heal, demonstrating impaired wound healing in the form of elastosis, myofiber disarray and scar formation (31, 97). Therefore, it is likely many of the biological changes associated with an invasive EVT phenotype occur secondary to this myometrial scarring and the resultant defective decidua (24). This is supported by our finding of increased ECM degradation in increta regions (Figure 3e).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

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“…Incomplete decidua in the invasive area results in direct contact between trophoblasts and myometrium, facilitating the interaction of immune environments from both sides and forming a distinctive microenvironment [ 16 , 17 ]. The microenvironment of invasive parts in PAS comprises a diverse array of cell populations, including trophoblasts, stromal cells, immune cells, and vascular components [ 18 – 20 ]. The hallmark of these invasive parts is characterized by sophisticated and multifaceted intercellular interactions.…”

Section: Introductionmentioning

confidence: 99%

Single-cell and spatial transcriptomics reveal alterations in trophoblasts at invasion sites and disturbed myometrial immune microenvironment in placenta accreta spectrum disorders

Ji,

Chen,

Pan

et al. 2024

Biomark Res

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Background Placenta accreta spectrum disorders (PAS) are a severe complication characterized by abnormal trophoblast invasion into the myometrium. The underlying mechanisms of PAS involve a complex interplay of various cell types and molecular pathways. Despite its significance, both the characteristics and intricate mechanisms of this condition remain poorly understood. Methods Spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq), were performed on the tissue samples from four PAS patients, including invasive tissues (ST, n = 3; scRNA-seq, n = 4), non-invasive normal placenta samples (ST, n = 1; scRNA-seq, n = 2). Three healthy term pregnant women provided normal myometrium samples (ST, n = 1; scRNA-seq, n = 2). ST analysis characterized the spatial expression landscape, and scRNA-seq was used to identify specific cellular components in PAS. Immunofluorescence staining was conducted to validate the findings. Results ST slices distinctly showed the myometrium in PAS was invaded by three subpopulations of trophoblast cells, extravillous trophoblast cells, cytotrophoblasts, and syncytiotrophoblasts, especially extravillous trophoblast cells. The pathways enriched by genes in trophoblasts, smooth muscle cells (SMC), and immune cells of PAS were mainly associated with immune and inflammation. We identified elevated expression of the angiogenesis-stimulating gene PTK2, alongside the cell proliferation-enhancing gene EGFR, within the trophoblasts of PAS group. Trophoblasts mainly contributed the enhancement of HLA-G and EBI3 signaling, which is crucial in establishing immune escape. Meanwhile, SMC regions in PAS exhibited upregulation of immunomodulatory markers such as CD274, HAVCR2, and IDO1, with CD274 expression experimentally verified to be increased in the invasive SMC areas of the PAS group. Conclusions This study provided information of cellular composition and spatial organization in PAS at single-cell and spatial level. The dysregulated expression of genes in PAS revealed a complex interplay between enhanced immune escape in trophoblasts and immune tolerance in SMCs during invasion in PAS. These findings will enhance our understanding of PAS pathogenesis for developing potential therapeutic strategies.

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Looking back to look forward: Has the time arrived for active management of obstetricians in placenta accreta spectrum?

Bartels,

Downey,

Brennan

2024

Intl J Gynecology & Obste

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Placenta accreta spectrum (PAS) is a relatively new obstetric condition which, until recently, was poorly understood. The true incidence is unknown because of the poor quality and heterogeneous diagnostic criteria. Classification systems have attempted to provide clarity on how to grade and diagnose PAS, but these are no longer reflective of our current understanding of PAS. This is particularly true for placenta percreta, which referred to extrauterine disease, as recent studies have demonstrated that placental villi associated with PAS have minimal potential to invade beyond the uterine serosa. It is accepted that PAS is a direct consequence of previous iatrogenic uterine injury, most commonly a previous cesarean section. Here, we “look back to look forwards”—starting with the primary predisposing factor for PAS, an iatrogenic uterine injury and subsequent wound healing. We then consider the evolution of definitions and diagnostic criteria of PAS from its first description over a century ago to current classifications. Finally, we discuss why modifications to the current classifications are needed to allow accurate diagnosis of this rare but life‐threatening complication, while avoiding overdiagnosis and potential patient harm.

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Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium

Cited by 8 publications

References 55 publications

Spatial proteomics and transcriptomics of placenta accreta spectrum

Spatial proteomics and transcriptomics of placenta accreta spectrum

Single-cell and spatial transcriptomics reveal alterations in trophoblasts at invasion sites and disturbed myometrial immune microenvironment in placenta accreta spectrum disorders

Looking back to look forward: Has the time arrived for active management of obstetricians in placenta accreta spectrum?

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