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

Endometriosis is characterized by growth of endometrial-like tissue outside of the uterus affecting many women during their reproductive age, causing years of pelvic pain and potential infertility. Its pathophysiology remains largely unknown, limiting early 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 122,000 cells across 14 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 an unreported progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment representing a comprehensive cell atlas of the disease in hormonally treated patients, essential information for advancing therapeutics and diagnostics. Overall design: Biopsies were collected from a total of 27 patients, 19 with confirmed endometriosis and 8 patients control. Biopsies were subjected to single cell experiments, bulk sequencing and cell hashing on patient-derived organoid. Single cells experiement were conducted on 31 biopsies consisting of 3 control and 9 eutopic endometrium, 8 ectopic peritoneal, 6 ectopic peritoneal adjacent, 4 ectopic ovary of endometriosis patient. A total of 24 biopsies were subjected to bulk sequencing, consist of 5 control and 7 eutopic endometrium, 6 ectopic peritoneal, 6 ectopic ovary of endometriosis patient. Single-cell cell hashing experiment were conducted on patient-derived organoid from 2 control and 4 eutopic endometrium, 4 ectopic peritoneum, 1 ectopic peritoneal adjacent of endometriosis patient. All single cell experiments were performed on 10x Genomics platform.

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