# A seed or soil problem in early endometriosis: stromal cell origin drives cellular invasion and coupling over mesothelial cell origin

## TL;DR

This study shows that endometrial stromal cells, not mesothelial cells, are the main drivers of early endometriosis lesion formation, suggesting new targets for diagnosis and treatment.

## Contribution

The study is the first to directly compare primary mesothelial and endometrial cells from endometriosis and control patients in invasion assays.

## Key findings

- Endometriosis stromal cells invade more than control stromal cells, regardless of mesothelial origin.
- Mesothelial cells from endometriotic lesion-affected areas show reduced ability to support invasion.
- Mesothelial cells enhance gap junction coupling in endometriosis stromal cells more than in control stromal cells.

## Abstract

To study the role of the mesothelial cells in early endometriosis lesion formation by assessing in vitro cell-to-cell communication and invasion of endometrial cells across a mesothelial cell monolayer, with both cell types derived from both patients with endometriosis and control patients.

Laboratory-based experimental study.

University hospital and laboratory.

Consenting reproductive-age women who underwent laparoscopy for gynecologic reasons and were confirmed to have either endometriosis with pathology tissue diagnosis (n = 8) or no endometriosis n = 8) at the time of surgery.

Primary stromal cells cultured from endometrial pipelle biopsies and primary mesothelial cells cultured from peritoneal explants were used in transmesothelial invasion assays and gap junction coupling assays.

Comparison of potential for lesion formation, using in vitro models, of both primary endometrial and mesothelial cells from patients with endometriosis and control patients, establishing the former as the primary disease driver.

When comparing mesothelial cells from control patients with those from patients with endometriosis, there was no significant difference in the amount of stromal cell invasion across either barrier. In contrast, when comparing stromal cell origin, the amount of invasion by endometriosis stromal cells was greater than control stromal cells regardless of whether the mesothelial cell monolayer was derived from patients with the disease or control patients. Additionally, primary mesothelial cells induced more gap junction coupling, a requirement for invasion, in stromal cells from patients with endometriosis than control patients, again independent of mesothelial origin. The notable exception was mesothelial cells derived from endometriotic lesion-affected areas that showed depressed ability to support invasion.

Although both endometrial and mesothelial cells need to function for establishment of endometriosis lesions, the endometrium seems to be the key player, serving as an ideal target for diagnostic strategies and therapeutic intervention. While this notion is consistent with previous studies, to our knowledge, we are the first to directly test both primary mesothelial and endometrial cells from patients with endometriosis and control patients to compare propensities for mesothelial invasion.