Epithelial cells that line the surface of the endometrium and carry specific protein markers could drive the formation of lesions outside the uterus in women with endometriosis, making them potential therapeutic targets for this condition, a study suggests.
The study, “Abnormally located SSEA1+/SOX9+ endometrial epithelial cells with a basalis-like phenotype in the eutopic functionalis layer may play a role in the pathogenesis of endometriosis,” was published in the journal Human Reproduction.
The premenopausal endometrium, or the inner lining of the uterus, contains epithelial cells in one of its layers, called the basalis. As a potential mechanism driving endometriosis, prior work proposed that women with this disorder have increased shedding of basalis-like cells combined with their functionalis — another layer of the endometrium — leading to the formation of ectopic (outside the uterus) endometriotic deposits in a process known as retrograde menstruation.
Cells that have the SSEA1 and nSOX9 protein markers are abundant in the basalis layer of the uterine endometrium. A similar cell phenotype, or set of characteristics, is found in ectopic endometriotic lesions. These cells, as well as epithelial cells expressing other markers, have shown or suggested activity critical for cellular proliferation in endometriosis.
A team of researchers from the U.K., U.S., and Australia used a baboon model of endometriosis that mimics retrograde menstruation to further study the role of SSEA1+/nSOX9+ epithelial cells in the development of the disease. They specifically examined if inducing ectopic endometriotic lesions increases the amount of epithelial cells with SSEA1 and nSOX9 in the uterine endometrium, as seen in patients.
The investigators also collected endometrial samples from 102 women, ranging in age from 18-55 — 44 with endometriosis (stage 2, or mild), at a mean age of 38 years, and 58 healthy controls, at a mean age of 41.5 years — to study whether endometriosis patients have excess levels of SSEA1+/nSOX9+ basalis-like epithelial cells in the secretory phase functionalis layer of the uterine endometrium and if these cells contribute to endometriosis lesions.
Of note, the secretory phase of the uterine cycle begins at ovulation and is characterized by maximal thickness of the endometrial lining.
In addition, the investigators assessed if SSEA1 levels differ in women with endometriosis compared with fertile women without the disorder. In vitro work using human cells explored if SSEA1+ endometrial epithelial cells are able to produce structures similar to ectopic endometriotic lesions.
Women with endometriosis showed higher numbers of basalis-like cells with SSEA1 and nSOX9 in the uterine endometrium’s functionalis layer than controls in the secretory phase of the cycle. Induction of endometriosis in the baboons led to a similar increase in basalis-like epithelial cells in the uterine endometrium, and of nSOX9-containing cells in ectopic endometriotic lesions.
Then, the team found that isolated SSEA1-containing epithelial cells from the uterine endometrium of women with endometriosis had markers of stem cell status, meaning they had the ability to differentiate, and a protein called FUT4 that could promote cell adhesion at ectopic sites.
Importantly, these cells differentiated into 3D gland-like structures in vitro — not into adipose or bone cells — showing “striking similarities with ectopic lesions,” according to the team.
As a result, this cell population “may generate ectopic lesions following retrograde menstruation,” and “may potentially be a therapeutic target for endometriosis,” the investigators said.
“Our data collectively suggest that shedding and retrograde menstruation of basalis-like cells is a prerequisite for ectopic lesion formation,” they wrote. “Our study, for the first time, provides an explanation of why 6–10% of women develop endometriosis when almost all undergo retrograde menstruation.”