Lesion-Specific Stromal Cell Behavior in Endometriosis

Endometriosis Stromal Cells Reveal Lesion-Specific Functional Heterogeneity

Key Points

Highlights: 

• Endometrial stromal cells (ESCs) exhibit lesion-type–specific functional phenotypes, with distinct patterns in migration, proliferation, contractility, and extracellular matrix remodeling—supporting biological heterogeneity across endometriosis subtypes.

Importance: 

• The findings provide mechanistic insight into lesion-specific disease behavior, linking cellular function to clinical heterogeneity and supporting the need for lesion-tailored therapeutic strategies.

What’s done here:

• Primary endometrial stromal cells were isolated from eutopic endometrium and different lesion types (superficial, deep infiltrating, endometrioma).
• Functional assays were performed to assess proliferation, migration, and contractility.
• Transcriptomic and proteomic analyses were conducted to identify lesion-specific molecular signatures
• Comparative analysis was performed to define phenotypic and molecular differences across lesion subtypes

Key results:

• ESCs from endometriotic lesions demonstrated a shift toward a migratory, less proliferative phenotype compared with eutopic cells.
• Endometrioma-derived ESCs showed the most pronounced migratory behavior but impaired gap closure efficiency.
• ESCs from superficial and deep lesions exhibited increased contractility, consistent with fibrotic remodeling and pain-related mechanisms.
• Distinct gene and protein expression profiles were identified across lesion types, particularly involving cell cycle regulation, extracellular matrix organization, adhesion, and metabolic pathways.
• Lesion-derived ESCs clustered separately, indicating biological divergence between lesion subtypes rather than a uniform disease process.

Strengths and Limitations:

• Strengths include the use of patient-derived primary cells preserving lesion-specific characteristics, combined with multi-layer functional and omics analyses.
• Limitations include the absence of truly healthy control endometrium and the use of in vitro systems that may not fully recapitulate the in vivo microenvironment.

From the Editor-in-Chief – EndoNews

"This study advances an important concept in endometriosis biology: that lesion heterogeneity is not merely morphological, but functionally encoded at the cellular level. By demonstrating that endometrial stromal cells (ESCs) derived from different lesion types exhibit distinct profiles of migration, proliferation, contractility, and extracellular matrix regulation, the work supports a model in which endometriosis represents a spectrum of biologically divergent microenvironments rather than a uniform disease entity.

A notable strength is the integration of functional assays with transcriptomic and proteomic analyses, allowing phenotypic observations to be anchored in molecular pathways. The identification of a migratory, low-proliferative phenotype in lesion-derived ESCs, alongside increased contractility in selected subtypes, aligns with mechanisms of invasion, fibrosis, and potentially pain generation. These findings are consistent with the clinical observation that different lesion types behave differently, yet they move the field beyond description toward mechanistic stratification.

Importantly, the study highlights the potential of patient-derived stromal cells as experimental models, preserving lesion-specific characteristics that are often lost in conventional systems. However, as with all in vitro approaches, the absence of the native microenvironment—including immune, neural, and hormonal interactions—limits direct translation to in vivo behavior. In addition, the lack of truly unaffected control endometrium constrains interpretation of disease-specific changes.

Overall, the data reinforce a shift toward lesion-informed and biology-driven frameworks in endometriosis research. Future studies will need to integrate stromal, immune, and neural components within spatial and in vivo contexts to determine how these cellular programs interact to shape clinical phenotypes."

Lay Summary

Endometriosis is known to present with highly variable clinical features, but the biological basis for this heterogeneity remains poorly understood.

A new study led by Brigitte Leeners from the University Hospital Zurich, Switzerland, and published in Cells, provides insight into how cellular behavior may differ across lesion types.

To investigate this, the researchers analyzed endometrial stromal cells (ESCs) isolated from different forms of endometriotic lesions—including superficial peritoneal lesions, deep infiltrating endometriosis, and endometriomas—as well as from eutopic endometrium.

They found that ESCs derived from endometriotic lesions display distinct functional properties. Compared with eutopic endometrial cells, lesion-derived ESCs showed reduced proliferative capacity but increased migratory behavior, suggesting a shift toward a more invasive cellular phenotype. This pattern was most pronounced in cells obtained from endometriomas.

In addition, ESCs from superficial and deep lesions exhibited increased contractility, a feature associated with tissue remodeling and fibrosis, which may contribute to pain generation. In contrast, this property was less evident in endometrioma-derived cells, highlighting functional divergence between lesion types.

Molecular analyses further supported these findings, revealing alterations in gene and protein expression related to cell cycle regulation, migration, and extracellular matrix organization. These results indicate that different endometriotic lesions are not biologically identical but instead exhibit distinct cellular programs.

The authors suggest that patient-derived stromal cells may serve as a valuable in vitro model to study the mechanisms underlying endometriosis heterogeneity. Overall, the findings provide a more nuanced understanding of disease biology and may contribute to the future development of more targeted diagnostic and therapeutic approaches.

Research Source: https://pubmed.ncbi.nlm.nih.gov/41369380/