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HOXC4 Promotes Proliferation of Endometriotic Stromal Cells via the SLIT2-ROBO1 Axis

ABSTRACT: Current interventions for endometriosis mainly involve hormone therapies but have limited efficacy and unacceptable side effects, due to the lack of selectivity to distinguish between endometriosis and endometrial tissues. Elucidating the molecular mechanism underlying rapid growth of endometrial-like stromal cells, one of the main components of endometriotic lesions, will pave a path for more effective treatment of endometriosis. In the current study, we utilized transcriptome sequencing to compare the transcriptional profiles of endometrial-like stromal cells from endometriosis and endometrial tissues and demonstrated that Homeobox C4 (HOXC4) is preferentially expressed in endometriotic lesions. HOXC4 is indispensable for the proliferation of stromal cells from endometriosis, but not those from endometrial tissues. Mechanistically, HOXC4 acts as a transcription factor to promote the expression of Slit Guidance Ligand 2 (SLIT2) and thereby, increases the p38 MAPK activity via the SLIT2 receptor Roundabout Guidance Receptor 1 (ROBO1). Considering the essential role of the p38 MAPK activity in facilitating the development of ectopic endometrium, our findings strongly support the idea of HOXC4, as well as the SLIT2-ROBO1 axis, being as potential therapeutic targets for endometriosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286315 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:Background Reduced endometrial receptivity is a major factor for impaired fertility in endometriosis (EMS). Endometrial deposition of collagen I proteins may account for poor endometrial receptivity in endometriosis. Methods We investigated the expression of collagen I expression in endometrium of endometriosis patients and in constructed EMS mice model. Effect of collagen I on ESCs was evaluated. Co-culture of exosomes with ESCs was conducted to evaluate the uptake of exosomes by different endometrial cell lines and the effect on decidualization of eutopic ESCs and embryo implantation. MiRNA expression profiles were compared between ectopic ESC derived exosomes and eutopic ESC derived exosomes. Luciferase reporter and its mutant plasmids were applied to confirm the direct target of miR-25-3p. Findings Here we found endometrial collagen I deposition with impaired decidualization in endometriosis patients and EMS mice model. Treatment of collagen I with ESCs contributed to impaired decidualization and inhibited BLS expansion in vitro. Endometriotic stromal cell-derived exosomes were detected in eutopic endometrium and the ectopic endometrial stromal cell derived exosomes were more taken-up by the same cell line in eutopic endometrium. Treatment of endometriotic stromal cell-derived exosomes increased the expression of endometrial collagen I in vitro and in vivo, while inhibited BLS expansion. Exosomal miR-25-3p was significantly increased in endometriotic stromal cell-derived exosomes compared with control group, and PTEN is a certain target of miR-25-3p. The promotion of endometrial miR-25-3p significantly increased collagen I expression in vitro through the PTEN/Akt pathway. Interpretation These results suggested that endometriotic stromal cell-derived exosomal miR-25-3p played key role in inducing endometrial collagen I deposition to impair embryo expansion in endometriosis via PTEN/Akt pathway. Funding National Nature Science Foundation of China (82271702), National Natural Science Foundation of China (81771537). Keywords: endometriosis; exosome; collagen I; miRNA; collagen deposition

Project description:Endometriosis is a debilitating gynecological disorder affecting approximately 10% of the female population. Despite its prevalence, robust methods to classify and treat endometriosis remain elusive. Changes throughout the menstrual cycle in tissue size, architecture, cellular composition, and individual cell phenotypes make it extraordinarily challenging to identify markers or cell types associated with uterine pathologies since disease-state alterations in gene and protein expression are convoluted with cycle phase variations. Here, we developed an integrated workflow to generate both proteomic and single-cell RNA-sequencing (scRNA-seq) data sets using tissues and cells isolated from the uteri of control and endometriotic donors. Using a linear mixed effect model (LMM), we identified proteins associated with cycle stage and disease, revealing a set of genes that drive separation across these two biological variables. Further, we analyzed our scRNA-seq data to identify cell types expressing cycle and disease- associated genes identified in our proteomic data. A module scoring approach was used to identify cell types driving the enrichment of certain biological pathways, revealing several pathways of interest across different cell subpopulations. Finally, we identified ligand-receptor pairs including Axl/Tyro3 – Gas6, that may modulate interactions between endometrial macrophages and/or endometrial stromal/epithelial cells. Analysis of these signaling pathways in an independent cohort of endometrial biopsies revealed a significant decrease in Tyro3 expression in patients with endometriosis compared to controls, both transcriptionally and through histological staining. This measured decrease in Tryo3 in patients with disease could serve as a novel diagnostic biomarker or treatment avenue for patients with endometriosis. Taken together, this integrated approach provides a framework for integrating LMMs, proteomic and RNA-seq data to deconvolve the complexities of complex uterine diseases and identify novel genes and pathways underlying endometriosis.

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HOXC4 Promotes Proliferation of Endometriotic Stromal Cells via the SLIT2-ROBO1 Axis

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