Multi-omics technology reveals the mechanism of endometrial decidualization resistance in patients with severe preeclampsia

Academic background

Preeclampsia (PE) is a common and serious complication during pregnancy, primarily characterized by hypertension, proteinuria, and dysfunction of other organs, posing a significant threat to maternal and fetal health. Among these, Severe Preeclampsia (SPE) represents a more dangerous form that can lead to life-threatening conditions for both the mother and the fetus. Although the pathogenesis of preeclampsia has not been fully elucidated, studies suggest that defects in endometrial decidualization may play an important role in its development. Decidualization refers to the functional changes occurring in the endometrium during early pregnancy, providing support for embryo implantation and placenta formation. Decidualization Resistance (DR) refers to the inability of the endometrium to undergo this process normally, leading to pregnancy failure or complications.

Previous research has shown that decidualization resistance is associated with various gynecological diseases and pregnancy complications, such as endometriosis and recurrent miscarriage. However, the specific molecular mechanisms of decidualization resistance in severe preeclampsia have not been fully understood. Therefore, this study aims to reveal the cellular and molecular characteristics of endometrial decidualization resistance in patients with severe preeclampsia through multi-omics technology, providing new insights into understanding its pathogenesis and offering potential targets for future clinical interventions.

Source of the paper

This paper was jointly completed by scientists including Irene Muñoz-Blat, Raúl Pérez-Moraga, Nerea Castillo-Marco from institutions such as the Carlos Simón Foundation in Spain, Incliva Health Research Institute, and the University of California, San Francisco. The study was published in February 2025 in the journal Nature Medicine, titled “Multi-omics-based mapping of decidualization resistance in patients with a history of severe preeclampsia”.

Research process and results

1. Study design and sample collection

The study included samples from multiple independent cohorts, including patients with severe preeclampsia (SPE) and normal pregnancy controls. Samples were collected from the endometrium of women during the late secretory phase of the menstrual cycle. The specific sample distribution is as follows:

• Digital image analysis: 11 SPE patients and 9 controls.
• Single-cell RNA sequencing (scRNA-seq): 11 SPE patients and 12 controls.
• Spatial transcriptomics: 8 SPE patients and 8 controls.
• Spatial proteomics: 7 SPE patients and 10 controls.

The study first observed the morphological features of the endometrium through digital image analysis (H&E stained sections), followed by scRNA-seq, spatial transcriptomics, and laser capture microdissection mass spectrometry (LCM-MS) technologies to reveal the molecular mechanisms of decidualization resistance at single-cell, spatial distribution, and protein levels.

2. Digital image analysis

The study first performed digital scanning on H&E stained endometrial sections and analyzed gland morphology using QuPath software. The results showed that the openings of the glands in SPE patients were significantly dilated, with smaller gland diameters and increased numbers of glandular epithelial cells. These morphological abnormalities suggest possible decidualization defects in the endometrium of SPE patients.

3. Single-cell RNA sequencing (scRNA-seq)

Through scRNA-seq technology, the study conducted single-cell transcriptome analysis on the endometrial cells of SPE patients and controls. A total of 65,381 high-quality cells were analyzed, including epithelial cells, stromal cells, endothelial cells, and immune cells. The results showed:

• Stromal cells: Stromal cells in SPE patients exhibited a “mosaic state,” where proliferative stromal cells (such as those expressing MMP11 and SFRP4) coexist with decidualized stromal cells (such as those expressing IGFBP1). This state indicates significant dysregulation in the decidualization process of stromal cells in SPE patients.
• Epithelial cells: In the epithelial cells of SPE patients, there was a significant increase in proliferative epithelial cells and ciliated epithelial cells, while glandular secretory epithelial cells decreased. This imbalance may affect the secretory function of the endometrium, thereby impacting embryo implantation.
• Epithelial-to-stromal transition (EMT): The EMT process was significantly reduced in SPE patients, indicating a lack of normal cell transformation ability during the decidualization process of the endometrium.

4. Spatial transcriptomics

To further validate the results of scRNA-seq, the study employed spatial transcriptomics technology to analyze endometrial tissue. The results showed significant gene expression dysregulation in both stromal and epithelial regions of the endometrium in SPE patients. For example, genes related to cytoskeletal organization (such as TPM1 and MYL9) were downregulated in the stromal region, while genes related to proliferation (such as MMP7) were upregulated in the epithelial region.

5. Spatial proteomics

Through LCM-MS technology, the study conducted proteomic analysis on the glandular epithelium, luminal epithelium, and stromal regions of the endometrium. The results showed that proteins related to hormone signaling pathways (such as STAT3 and ESR1) were significantly upregulated in the stromal region of SPE patients, while proteins related to extracellular matrix organization were downregulated. Additionally, proteins related to cell survival and oxidative stress responses were significantly increased in the glandular epithelial region of SPE patients.

Conclusion and significance

This study comprehensively revealed the molecular mechanisms of endometrial decidualization resistance in patients with severe preeclampsia through multi-omics technology. The study found significant imbalances in proliferation and differentiation in both stromal and epithelial cells of the endometrium in SPE patients, with disruptions in hormone signaling pathways (especially estrogen and progesterone signals). These findings not only deepen the understanding of the pathogenesis of severe preeclampsia but also provide potential targets for developing clinical intervention strategies targeting decidualization resistance in the future.

Highlights of the study

1. Combined application of multi-omics technologies: This study is the first to integrate scRNA-seq, spatial transcriptomics, and LCM-MS technologies to comprehensively analyze the molecular mechanisms of decidualization resistance.
2. Revealing imbalance in cell proliferation and differentiation: The study found significant imbalances in proliferation and differentiation in the endometrial cells of SPE patients, providing a new perspective for understanding their pathological mechanisms.
3. Key role of hormone signaling pathways: The study emphasized the central role of estrogen and progesterone signaling pathways in decidualization resistance, offering important clues for future clinical interventions.

Application value

This study not only provides new insights into the pathological mechanisms of severe preeclampsia but also serves as an important reference for research on other gynecological diseases related to decidualization resistance (such as endometriosis and recurrent miscarriage). Moreover, the molecular markers discovered in this study could serve as potential targets for future clinical diagnosis and treatment, helping to improve pregnancy outcomes and female reproductive health.

Other valuable information

The source of samples in this study is extensive, covering multiple independent cohorts, ensuring the reliability and universality of the results. Additionally, the research team developed deep learning-based image analysis algorithms, providing new tools for quantitative analysis of endometrial morphology. The application of these technologies and methods offers important technical support for future related research.