Single-cell analysis of endometriosis reveals a coordinated transcriptional programme driving immunotolerance and angiogenesis across eutopic and ectopic tissues

Abstract

Endometriosis is characterized by growth of endometrial-like tissue outside of the uterus affecting many women in their reproductive age, causing years of pelvic pain and potential infertility. Its pathophysiology remains largely unknown, limiting diagnosis and treatment. We characterized peritoneal and ovarian lesions at single-cell transcriptome resolution and compared to matched eutopic endometrium, control endometrium, and organoids derived from these tissues, generating data on over 100,000 cells across 12 individuals. We spatially localized many of the cell types using imaging mass cytometry. We identify a perivascular mural cell unique to the peritoneal lesions with dual roles in angiogenesis promotion and immune cell trafficking. We define an immunotolerant peritoneal niche, fundamental differences in eutopic endometrium and between lesions microenvironments, and a novel progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment representing the first comprehensive cell atlas of the disease, essential information for advancing therapeutics and diagnostics.

Niclosamide targets the dynamic progression of macrophages for the resolution of endometriosis in a mouse model

“…Abnormal activation and increased numbers of macrophages along with elevated levels of proinflammatory cytokines such as IL-1β, IL6, IL8, and TNFα are present in the peritoneal fluid of patients with endometriosis 11 , 43 , 44 . Moreover, analysis of macrophages within the pelvic cavity and endometriotic lesions of patients has demonstrated enhanced biological activities related to angiogenesis, neurogenesis, antigen processing and presentation, and tissue adhesion 45 , 46 . Our previous studies in mice have demonstrated that niclosamide treatment reduced inflammation in the peritoneal fluid, lesions, pelvic organs (uterus and vagina), and dorsal root ganglion 5 .…”

“…The heterogeneity of macrophages in the human endometriotic microenvironment shares some similar characteristics with those found within the murine peritoneal cavity in this study. In the pelvic cavity and eutopic and ectopic endometrium of endometriosis patients, both CCR2 + monocyte-derived and tissueresident macrophages were distinguished using scRNA-seq and traditional methods such as flow cytometry 45,46,[58][59][60] . FOLR2 + macrophages were also identified in the endometriotic lesions in patients 46 .…”

“…In the pelvic cavity and eutopic and ectopic endometrium of endometriosis patients, both CCR2 + monocyte-derived and tissueresident macrophages were distinguished using scRNA-seq and traditional methods such as flow cytometry 45,46,[58][59][60] . FOLR2 + macrophages were also identified in the endometriotic lesions in patients 46 . However, they have been considered as a resident subtype based on the expression of FOLR2 and localization within cancerous tumours 56,61 , which may not consider the variation of FOLR2 expression in tissues of other locations.…”

Transcriptome Profiling of Eutopic and Ectopic Endometrial Stromal Cells in Women with Endometriosis Based on High-Throughput Sequencing

“…They concluded that immune dysfunction may play an important role in the pathology of endometriosis. Moreover, Tan Y et al analyzed the transcriptome of endometrium and endometriotic lesions using single-cell RNA sequencing and provided a landscape of the endometriosis microenvironment [ 14 ]. In general, evaluating transcriptome datasets facilitates the assessment of overall gene functions and structures to investigate the molecular signatures predictive of certain diseases.…”

Decoding the endometrial niche of Asherman’s Syndrome at single-cell resolution

“…Although bulk tissuebased transcriptomics studies [12][13][14] have revealed basic information, convincing evidence regarding the molecular mechanisms involved in AS-related endometrial dysfunction remains elusive. Advancements in single-cell RNA sequencing (scRNA-seq) of the human endometrium 15 and endometrial organoid culture systems 16 have enabled a deeper understanding of cellular cartography and cell-to-cell communication (CCC) in endometrial pathologies such as endometriosis 17 and atrophic endometrium 18 .…”