Single-cell Analysis of Endometriosis Reveals a Coordinated Transcriptional Programme Driving Immunotolerance and Angiogenesis Across Eutopic and Ectopic Tissues

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2022 Jul 21

PMID 35864314

Authors

Yuliana Tan

William F Flynn

Santhosh Sivajothi

Diane Luo

Suleyman B Bozal

Monica Dave

Anthony A Luciano

Paul Robson

Danielle E Luciano

Elise T Courtois

Affiliations

Soon will be listed here.

Abstract

Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus. It affects many women during their reproductive age, causing years of pelvic pain and potential infertility. Its pathophysiology remains largely unknown, which limits early diagnosis and treatment. We characterized peritoneal and ovarian lesions at single-cell transcriptome resolution and compared them to matched eutopic endometrium, unaffected 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 specific 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 lesion microenvironments and an unreported progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment that represents a comprehensive cell atlas of the disease in individuals undergoing hormonal treatment, providing essential information for future therapeutics and diagnostics.

Citing Articles

Integration of Single Cell and Bulk RNA-Sequencing Reveals Key Genes and Immune Cell Infiltration to Construct a Predictive Model and Identify Drug Targets in Endometriosis.

Zhang H, Fang Y, Luo D, Li Y J Inflamm Res. 2025; 18:2783-2804.

PMID: 40026309 PMC: 11871914. DOI: 10.2147/JIR.S497643.

Systematic review on the DNA methylation role in endometriosis: current evidence and perspectives.

Ducreux B, Patrat C, Firmin J, Ferreux L, Chapron C, Marcellin L Clin Epigenetics. 2025; 17(1):32.

PMID: 39985111 PMC: 11846336. DOI: 10.1186/s13148-025-01828-w.

Single-cell transcriptomic atlas of different endometriosis indicating that an interaction between endometriosis-associated mesothelial cells (EAMCs) and ectopic stromal cells may influence progesterone resistance.

Hou S, Zhang J, Zhang Z, Qu H, Li S, Jiang Y Clin Transl Med. 2025; 15(2):e70216.

PMID: 39968688 PMC: 11836620. DOI: 10.1002/ctm2.70216.

Mapping Human Uterine Disorders Through Single-Cell Transcriptomics.

Boldu-Fernandez S, Lliberos C, Simon C, Mas A Cells. 2025; 14(3).

PMID: 39936948 PMC: 11817058. DOI: 10.3390/cells14030156.

Spatial transcriptomic analysis identifies epithelium-macrophage crosstalk in endometriotic lesions.

Burns G, Fu Z, Vegter E, Madaj Z, Greaves E, Flores I iScience. 2025; 28(2):111790.

PMID: 39935459 PMC: 11810701. DOI: 10.1016/j.isci.2025.111790.

References

Samaniego R, Dominguez-Soto A, Ratnam M, Matsuyama T, Sanchez-Mateos P, Corbi A . Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1. Cells. 2020; 9(6). PMC: 7349916. DOI: 10.3390/cells9061445. View

Maier B, Leader A, Chen S, Tung N, Chang C, LeBerichel J . A conserved dendritic-cell regulatory program limits antitumour immunity. Nature. 2020; 580(7802):257-262. PMC: 7787191. DOI: 10.1038/s41586-020-2134-y. View

Villar J, Segura E . Decoding the Heterogeneity of Human Dendritic Cell Subsets. Trends Immunol. 2020; 41(12):1062-1071. DOI: 10.1016/j.it.2020.10.002. View

Paulsen F, Woon C, Varoga D, Jansen A, Garreis F, Jager K . Intestinal trefoil factor/TFF3 promotes re-epithelialization of corneal wounds. J Biol Chem. 2008; 283(19):13418-27. PMC: 2442345. DOI: 10.1074/jbc.M800177200. View

Kang T, Bocci F, Jolly M, Levine H, Onuchic J, Levchenko A . Pericytes enable effective angiogenesis in the presence of proinflammatory signals. Proc Natl Acad Sci U S A. 2019; 116(47):23551-23561. PMC: 6876202. DOI: 10.1073/pnas.1913373116. View

Boretto M, Maenhoudt N, Luo X, Hennes A, Boeckx B, Bui B . Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat Cell Biol. 2019; 21(8):1041-1051. DOI: 10.1038/s41556-019-0360-z. View

Ziegenhain C, Sandberg R . BAMboozle removes genetic variation from human sequence data for open data sharing. Nat Commun. 2021; 12(1):6216. PMC: 8553849. DOI: 10.1038/s41467-021-26152-8. View

Lim H, Lim S, Tan C, Thiam C, Goh C, Carbajo D . Hyaluronan Receptor LYVE-1-Expressing Macrophages Maintain Arterial Tone through Hyaluronan-Mediated Regulation of Smooth Muscle Cell Collagen. Immunity. 2018; 49(2):326-341.e7. DOI: 10.1016/j.immuni.2018.06.008. View

Gustafsson C, Mjosberg J, Matussek A, Geffers R, Matthiesen L, Berg G . Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS One. 2008; 3(4):e2078. PMC: 2323105. DOI: 10.1371/journal.pone.0002078. View

10.

Taupin D, Podolsky D . Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol. 2003; 4(9):721-32. DOI: 10.1038/nrm1203. View

11.

Edwards A, Ramesh S, Singh V, Tayade C . A peptide inhibitor of synuclein-γ reduces neovascularization of human endometriotic lesions. Mol Hum Reprod. 2014; 20(10):1002-8. PMC: 4172171. DOI: 10.1093/molehr/gau054. View

12.

Sharma A, Seow J, Dutertre C, Pai R, Bleriot C, Mishra A . Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. Cell. 2020; 183(2):377-394.e21. DOI: 10.1016/j.cell.2020.08.040. View

13.

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

14.

Lain E, Carnejac S, Escher P, Wilson M, Lomo T, Gajendran N . A novel role for embigin to promote sprouting of motor nerve terminals at the neuromuscular junction. J Biol Chem. 2009; 284(13):8930-9. PMC: 2659250. DOI: 10.1074/jbc.M809491200. View

15.

Zondervan K, Becker C, Koga K, Missmer S, Taylor R, Vigano P . Endometriosis. Nat Rev Dis Primers. 2018; 4(1):9. DOI: 10.1038/s41572-018-0008-5. View

16.

Vento-Tormo R, Efremova M, Botting R, Turco M, Vento-Tormo M, Meyer K . Single-cell reconstruction of the early maternal-fetal interface in humans. Nature. 2018; 563(7731):347-353. PMC: 7612850. DOI: 10.1038/s41586-018-0698-6. View

17.

Cindrova-Davies T, Zhao X, Elder K, Jones C, Moffett A, Burton G . Menstrual flow as a non-invasive source of endometrial organoids. Commun Biol. 2021; 4(1):651. PMC: 8211845. DOI: 10.1038/s42003-021-02194-y. View

18.

Bergen V, Lange M, Peidli S, Wolf F, Theis F . Generalizing RNA velocity to transient cell states through dynamical modeling. Nat Biotechnol. 2020; 38(12):1408-1414. DOI: 10.1038/s41587-020-0591-3. View

19.

Rodda L, Lu E, Bennett M, Sokol C, Wang X, Luther S . Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity. Immunity. 2018; 48(5):1014-1028.e6. PMC: 5971117. DOI: 10.1016/j.immuni.2018.04.006. View

20.

Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y . A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021; 184(3):792-809.e23. DOI: 10.1016/j.cell.2021.01.010. View