Cellular Interactions Driving Peritoneal Endometriosis

Unlocking Disease Progression in Endometriosis Through Spatial Transcriptomics

Key Points

Highlight:

• Peritoneal endometriosis epithelium plays a crucial role in modulating immune responses and promoting a pro-repair macrophage phenotype.

Importance:

• This study highlights the value of spatial transcriptomics in understanding the cellular interactions that drive inflammation in endometriotic lesions.

What’s done here:

• Spatial transcriptomics, bulk RNA sequencing, and receptor-ligand analysis were used to compare gene expression between superficial peritoneal endometriotic lesions and matched eutopic endometrium from the same patients.

Key results:

• Stromal gene expression in endometriotic lesions was largely similar to that of the eutopic endometrium.
• Increased expression of immune response genes, including C3 and MHC class II-related markers, was observed in the endometriosis epithelium.
• Epithelium-to-macrophage inflammatory signaling was nearly 4x higher in endometriotic lesions suggesting the central role of epithelial cells in driving inflammation and promoting a pro-repair macrophage phenotype.

Strengths and Limitations

• The paired design reducing variability and the use of multiple techniques providing detailed insights are strengths of the stydt.
• The lack of healthy controls, limited clinical data, small sample size, and potential age-related dysfunctions may be the limitation.

Lay Summary

A recent study led by Dr.Fazlaebas from the USA, published in the January 2025 issue of iScience, einvestigated the genes and cellular pathways involved in the development of peritoneal endometriosis. Using spatial transcriptomics, the study identified cell type-specific gene expression changes and examined the interactions between the stroma, epithelium, and macrophages, comparing to the eutopic endometrium from the same patients.

The findings revealed significant transcriptional similarities between the lesions and eutopic endometrium, particularly in the sub-epithelial stroma and epithelium, despite the lesions' inflammatory and fibrotic nature. Gene expression differences were most pronounced in the macrophage compartment, with peritoneal and monocyte-derived macrophages present in the lesions, contrasting with tissue-resident macrophages in the eutopic endometrium.

The study highlighted increased signaling between the lesion epithelium and macrophages, indicating the epithelium’s central role in driving inflammation. Receptor-ligand analysis showed a nearly 4x increase in epithelial-macrophage signaling, with MHC-II ligands in the lesion epithelium interacting with CD4 receptors on macrophages, likely promoting monocyte differentiation into macrophages and sustaining inflammation. 

Furthermore, complement component 3 (C3) expression was notably higher in the endometriotic epithelium, supporting a pro-repair macrophage phenotype that contributes to tissue remodeling, neovascularization, and fibrosis. Additionally, macrophage migration inhibitory factor (MIF) signaling was identified as a key pathway promoting local inflammation and enhancing prostaglandin E2 secretion. 

The study underscores the value of spatial transcriptomics in understanding the cellular interactions within endometriotic lesions. It concludes that the lesion epithelium orchestrates inflammatory signaling and macrophage phenotype modulation, suggesting further investigation into these processes for potential therapeutic targets.

Research Source: https://pubmed.ncbi.nlm.nih.gov/39935459/