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18 pages, 3299 KiB

Open AccessArticle

Endometriotic Follicular Fluid Affects Granulosa Cells’ Morphology and Increases Duplication Rate and Connexin-43 Expression

by Loris Marin, Chiara Sabbadin, Giovanni Faggin, Claudia Maria Radu, Decio Armanini, Michele Paccagnella, Cristiano Salata, Luciana Bordin, Eugenio Ragazzi, Guido Ambrosini and Alessandra Andrisani

Biomolecules 2025, 15(4), 561; https://doi.org/10.3390/biom15040561 - 10 Apr 2025

Viewed by 358

Abstract

Endometriosis is a complicated condition characterized by inflammation, low oocyte quality, and decreased uterus receptivity, associated with fertility issues. This study aims to better understand the reduced pregnancy outcome in endometriosis by analyzing both the granulosa cells (GCs) and the follicular fluids (FFs) [...] Read more.

Endometriosis is a complicated condition characterized by inflammation, low oocyte quality, and decreased uterus receptivity, associated with fertility issues. This study aims to better understand the reduced pregnancy outcome in endometriosis by analyzing both the granulosa cells (GCs) and the follicular fluids (FFs) obtained during the assisted reproductive technology (ART)-related oocyte pick-up. Seventy patients, approaching our ART Center with the diagnosis of infertility for Age-Idiopathic Factor (AIF) (n = 36), endometriosis (ENDO) (n = 23), or male factor (MF) (n = 11), were enrolled in this study. GCs from each group were separately analyzed for morphology, replication, and expression of Connexin-43 and Follicle-Stimulating Hormone Receptor (FSHR) by microscopy, flow cytometry, and immunocytochemistry. Results show that FF in a culture medium allowed GCs to survive and replicate. Upon culturing GCs from each group with ENDO follicular fluid, increases were observed in both population doublings and in the development of fibroblast-like and muscle-like morphologies. Despite undergoing morphological changes, GCs consistently expressed FSHR. However, exposure to ENDO follicular fluid led to an upregulation of Connexin-43 expression across all GC groups. These findings suggest that in endometriosis, FF contains unidentified factors that can induce aberrant replication, morphological differentiation, and overexpression of Connexin-43, potentially contributing to follicular dysfunction. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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14 pages, 914 KiB

Open AccessArticle

Quantification of Free Circulating DNA and Differential Methylation Profiling of Selected Genes as Novel Non-Invasive Biomarkers for Endometriosis Diagnosis

by Moncef Benkhalifa, Pierre Alain Menoud, David Piquemal, Jack Y. Hazout, Sami Mahjoub, Mohammed Zarquaoui, Noureddine Louanjli, Rosalie Cabry and Andre Hazout

Biomolecules 2025, 15(1), 69; https://doi.org/10.3390/biom15010069 - 6 Jan 2025

Viewed by 1231

Abstract

Endometriosis is a chronic, estrogen-dependent disorder associated with the presence of endometrial cells mainly in the pelvic cavity, causing systemic immune inflammation, infertility, epigenetic dysregulation of differential DNA methylation, coelomic metaplasia, and pain. It affects approximately 10–12% of women. Despite decades of research, [...] Read more.

Endometriosis is a chronic, estrogen-dependent disorder associated with the presence of endometrial cells mainly in the pelvic cavity, causing systemic immune inflammation, infertility, epigenetic dysregulation of differential DNA methylation, coelomic metaplasia, and pain. It affects approximately 10–12% of women. Despite decades of research, full pathophysiology, a diagnostic roadmap, and clinical management strategies for endometriosis are not yet fully elucidated. Cell-free DNA (Cf-DNA) in the peripheral blood of diseased and healthy individuals was discovered in the 1950s. Quantifying peripheral Cf-DNA and the specific differential methylation of a group of genes have been proposed as potential non-invasive diagnostic biomarkers for somatic and constitutional genetics and for various other pathological disorders. In this study, we investigated the Cf-DNA levels of 78 young women, 38 of whom had endometriosis confirmed via laparoscopy and 40 of whom were healthy. We found a significant difference between the two groups when Cf-DNA was quantified, with 3.9 times more Cf-DNA in the serum of women with endometriosis. We also identified nine target genes potentially involved in the pathogenesis of endometriosis, with a different methylation profile between the two groups. Our data suggest that the combination of cell-free DNA quantification and the assessment of the epigenetic signature of differential methylation of nine genes can be proposed as a non-invasive predictive and diagnostic test for endometriosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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16 pages, 3890 KiB

Open AccessArticle

miR-193b-5p and miR-374b-5p Are Aberrantly Expressed in Endometriosis and Suppress Endometrial Cell Migration In Vitro

by Caroline Frisendahl, Yiqun Tang, Nageswara Rao Boggavarapu, Maire Peters, Parameswaran Grace Lalitkumar, Terhi T. Piltonen, Riikka K. Arffman, Andres Salumets, Martin Götte, Eberhard Korsching and Kristina Gemzell-Danielsson

Biomolecules 2024, 14(11), 1400; https://doi.org/10.3390/biom14111400 - 3 Nov 2024

Viewed by 1819

Abstract

(1) Background: Endometriosis is a highly prevalent gynecological disease affecting 10% of women of reproductive age worldwide. miRNAs may play a role in endometriosis, though their exact function remains unclear. This study aimed to identify differentially expressed miRNAs in endometriosis and study their [...] Read more.

(1) Background: Endometriosis is a highly prevalent gynecological disease affecting 10% of women of reproductive age worldwide. miRNAs may play a role in endometriosis, though their exact function remains unclear. This study aimed to identify differentially expressed miRNAs in endometriosis and study their functions in the disease. (2) Methods: Endometrial tissue was collected from women with endometriosis (n = 15) and non-endometriosis controls (n = 17). Dysregulated miRNAs were identified through small RNA-sequencing, and their biological significance was explored by target gene prediction and pathway analysis. Selected miRNAs were examined in paired ectopic endometriomas and eutopic endometrium (n = 10) using qRT-PCR. Their roles in cell migration and proliferation were further examined in vitro using functional assays. To identify potential target genes, we performed mRNA sequencing on transfected cells and the endometrioma cohort. (3) Results: We identified 14 dysregulated miRNAs in the eutopic endometrium of women with endometriosis compared to endometrial tissue from women without endometriosis. Pathway analysis indicated enrichment in cell migration and proliferation-associated pathways. Further ex vivo studies of miR-193b-5p and miR-374b-5p showed that both miRNAs were upregulated in endometrioma. Overexpression of these two miRNAs in vitro inhibited cell migration, and mRNA sequencing revealed several migration-related genes that are targeted by these miRNAs. (4) Conclusions: Our study identified two key endometrial miRNAs that may be involved in the pathogenesis of endometriosis by regulating cell migration. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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15 pages, 4079 KiB

Open AccessArticle

Characterization of E-Cadherin, SSEA-1, MSI-1, and SOX-2 Expression and Their Association with Pale Cells in Adenomyosis

by Jingjun Tian, Veronika Hoffmann, Mohamed Gamal Ibrahim, Uwe Hansen, Andreas N. Schüring, Renata Voltolini Velho, Sylvia Mechsner and Martin Götte

Biomolecules 2024, 14(11), 1355; https://doi.org/10.3390/biom14111355 - 24 Oct 2024

Viewed by 1534

Abstract

Adenomyosis (AM) is a gynecological disease characterized by the invasion of endometrial glands and stroma within the myometrium. The etiology and pathogenesis of AM remain inadequately understood. Pale cells were identified as a novel cell type characterized by the absence of desmosomal contacts [...] Read more.

Adenomyosis (AM) is a gynecological disease characterized by the invasion of endometrial glands and stroma within the myometrium. The etiology and pathogenesis of AM remain inadequately understood. Pale cells were identified as a novel cell type characterized by the absence of desmosomal contacts and light-colored cytoplasm. These cells were observed to migrate individually through ultra-micro ruptures in the basal membrane of the endometrial glands, translocating into the stroma and then further into the myometrium. Our study aimed to explore the possible stem cell properties of these pale cells. Forty hysterectomy specimens were analyzed using immunohistochemistry and immunofluorescence to assess negative E-cadherin expression and the positive expression of stem cell markers SSEA-1, MSI-1, and SOX-2. Immunohistochemical analysis revealed the presence of pale cells and occasionally rounded, enlarged E-cadherin-negative cells predominantly in the basal endometrial epithelium. The stem cell marker SSEA-1 was significantly elevated in the basalis epithelium, as well as in the ectopic epithelium. SSEA-1 positive cells were also identified in the stroma and myometrium. Sporadic colocalization of SSEA-1+/E-cadherin– cells was confirmed through immunofluorescence. The positive staining of pale cells for SSEA-1 and MSI-1 was also confirmed at the ultrastructural level by immunoelectron microscopy. These findings indicate that pale cells may possess stem cell characteristics, particularly a positive SSEA-1 profile, warranting further in vitro investigation into their role in the pathogenesis of adenomyosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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13 pages, 7099 KiB

Open AccessArticle

Assessment of the Ferroptosis Regulators: Glutathione Peroxidase 4, Acyl-Coenzyme A Synthetase Long-Chain Family Member 4, and Transferrin Receptor 1 in Patient-Derived Endometriosis Tissue

by Lidia A. Mielke Cabello, Gabriela Meresman, Dogus Darici, Noelia Carnovale, Birthe Heitkötter, Miriam Schulte, Nancy A. Espinoza-Sánchez, Quang-Khoi Le, Ludwig Kiesel, Sebastian D. Schäfer and Martin Götte

Biomolecules 2024, 14(7), 876; https://doi.org/10.3390/biom14070876 - 21 Jul 2024

Viewed by 2105

Abstract

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, [...] Read more.

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, may contribute to the progression of endometriosis. This retrospective case–control study provides a comprehensive immunohistochemical assessment of the expression and tissue distribution of established ferroptosis markers: GPX4, ACSL4, and TfR1 in endometriosis patients. The case group consisted of 38 women with laparoscopically and histologically confirmed endometriosis and the control group consisted of 18 women with other gynecological conditions. Our study revealed a significant downregulation of GPX4 in stromal cells of endometriosis patients (M = 59.7% ± 42.4 versus 90.0% ± 17.5 in the control group, t (54) = −2.90, p = 0.005). This finding aligned with slightly, but not significantly, higher iron levels detected in the blood of endometriosis patients, using hemoglobin as an indirect predictor (Hb 12.8 (12.2–13.5) g/dL versus 12.5 (12.2–13.4) g/dL in the control group; t (54) = −0.897, p = 0.374). Interestingly, there was no concurrent upregulation of TfR1 (M = 0.7 ± 1.2 versus 0.2 ± 0.4 for EM, t (54) = 2.552, p = 0.014), responsible for iron uptake into cells. Our empirical findings provide support for the involvement of ferroptosis in the context of endometriosis. However, variances in expression patterns within stromal and epithelial cellular subsets call for further in-depth investigations. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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14 pages, 5848 KiB

Open AccessArticle

Estetrol Inhibits Endometriosis Development in an In Vivo Murine Model

by Ana Sofia Zabala, Rocío Ayelem Conforti, María Belén Delsouc, Verónica Filippa, Maria Magdalena Montt-Guevara, Andrea Giannini, Tommaso Simoncini, Sandra Silvina Vallcaneras and Marilina Casais

Biomolecules 2024, 14(5), 580; https://doi.org/10.3390/biom14050580 - 15 May 2024

Cited by 3 | Viewed by 2664

Abstract

Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, and it is associated with alterations in the expression of hormone receptors and inflammation. Estetrol (E₄) is a weak estrogen that recently has been approved for contraception. We evaluated [...] Read more.

Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, and it is associated with alterations in the expression of hormone receptors and inflammation. Estetrol (E₄) is a weak estrogen that recently has been approved for contraception. We evaluated the effect of E₄ on the growth of endometriotic-like lesions and the expression of TNF-α, estrogen receptors (ERs), and progesterone receptors (PRs) in an in vivo murine model. Endometriosis was induced surgically in female C57BL/6 mice. E₄ was delivered via Alzet pump (3 mg/kg/day) from the 15th postoperative day for 4 weeks. E₄ significantly reduced the volume (p < 0.001) and weight (p < 0.05) of ectopic lesions. Histologically, E₄ did not affect cell proliferation (PCNA immunohistochemistry) but it did increase cell apoptosis (TUNEL assay) (p < 0.05). Furthermore, it modulated oxidative stress (SOD, CAT, and GPX activity, p < 0.05) and increased lipid peroxidation (TBARS/MDA, p < 0.01). Molecular analysis showed mRNA (RT-qPCR) and protein (ELISA) expression of TNF-α decreased (p < 0.05) and mRNA expression of Esr2 reduced (p < 0.05), in contrast with the increased expression of Esr1 (p < 0.01) and Pgr (p < 0.05). The present study demonstrates for the first time that E₄ limited the development and progression of endometriosis in vivo. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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Review

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17 pages, 2097 KiB

Open AccessReview

Regulated Cell Death in Endometriosis

by Erqing Huang, Xiaoli Wang and Lijuan Chen

Biomolecules 2024, 14(2), 142; https://doi.org/10.3390/biom14020142 - 23 Jan 2024

Cited by 8 | Viewed by 3474

Abstract

Regulated cell death (RCD) represents a distinct mode of cell demise, differing from accidental cell death (ACD), characterized by specific signaling cascades orchestrated by diverse biomolecules. The regular process of cell death plays a crucial role in upholding internal homeostasis, acting as a [...] Read more.

Regulated cell death (RCD) represents a distinct mode of cell demise, differing from accidental cell death (ACD), characterized by specific signaling cascades orchestrated by diverse biomolecules. The regular process of cell death plays a crucial role in upholding internal homeostasis, acting as a safeguard against biological or chemical damage. Nonetheless, specific programmed cell deaths have the potential to activate an immune–inflammatory response, potentially contributing to diseases by enlisting immune cells and releasing pro-inflammatory factors. Endometriosis, a prevalent gynecological ailment, remains incompletely understood despite substantial progress in unraveling associated signaling pathways. Its complexity is intricately tied to the dysregulation of inflammatory immune responses, with various RCD processes such as apoptosis, autophagic cell death, pyroptosis, and ferroptosis implicated in its development. Notably, limited research explores the association between endometriosis and specific RCD pathways like pyroptosis and cuproptosis. The exploration of regulated cell death in the context of endometriosis holds tremendous potential for further advancements. This article thoroughly reviews the molecular mechanisms governed by regulated cell death and their implications for endometriosis. A comprehensive understanding of the regulated cell death mechanism in endometriosis has the potential to catalyze the development of promising therapeutic strategies and chart the course for future research directions in the field. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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13 pages, 631 KiB

Open AccessReview

The Extracellular Vesicle–Macrophage Regulatory Axis: A Novel Pathogenesis for Endometriosis

by Xiaoxiao Gao, Han Gao, Wei Shao, Jiaqi Wang, Mingqing Li and Songping Liu

Biomolecules 2023, 13(9), 1376; https://doi.org/10.3390/biom13091376 - 12 Sep 2023

Cited by 8 | Viewed by 2437

Abstract

Endometriosis (EMs) is a common disease among women whose pathogenesis is still unclear, although there are various hypotheses. Recent studies have considered macrophages the key part of the immune system in developing EMs, inducing inflammation, the growth and invasion of the ectopic endometrium, [...] Read more.

Endometriosis (EMs) is a common disease among women whose pathogenesis is still unclear, although there are various hypotheses. Recent studies have considered macrophages the key part of the immune system in developing EMs, inducing inflammation, the growth and invasion of the ectopic endometrium, and angiogenesis. Extracellular vesicles (EVs) as novel intercellular vesicle traffic, can be secreted by many kinds of cells, including macrophages. By carrying long non-coding RNA (lncRNA), microRNA (miRNA), or other molecules, EVs can regulate the biological functions of macrophages in an autocrine and paracrine manner, including ectopic lesion growth, immune dysfunction, angiogenesis, and can further accelerate the progression of EMs. In this review, the interactions between macrophages and EVs for the pathogenesis of EMs are summarized. Notably, the regulatory pathways and molecular mechanisms of EVs secreted by macrophages during EMs are reviewed. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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