TABLE 2.
Recent single cell analyses of endometriosis lesions.
| Reference | Tissue analyzed | Total cells sequenced | Technology/Platform | Total subjects | Endometriosis type and ASRM Stage | Controls | Race/Ethnicity | Hormones/IUD | Cycle phase endometrial histology | Main findings |
|---|---|---|---|---|---|---|---|---|---|---|
| Ma 2021 | Endometrium, ovarian endometrioma | 55 000 | scRNAseq (10X) | n = 6 subjects (n = 3 cases, n = 3 controls) | ASRM Stage III, IV ovarian endometriomas | Healthy controls without endometriosis | N/A | None | All in proliferative phase | Fibroblasts: heterogeneous populations with clusters: cytokine. inflammatory response; FGF, immune response; ECM, cell adhesion; angiogenesis, hypoxia. All MAPK, TNF, IL‐17. TGFβ signaling, high expression of StAR. Immune populations: uNK cell frequency in EuE normal > EuE disease > endometrioma. Fewer T cells and uNK cells are more active, Mϕ enriched in tissue remodeling in lesion vs Eu E. Conclusion: FB and immune sub‐populations contribute a pro‐inflammatory, angiogenic environment in endometriomas. |
| Garcia‐Alonso 2022 | Endometrium (functionalis, full thickness), endometriosis peritoneal lesions (red, white, black) | 98 569 | scRNAseq, snRNA seq, spatial profiling. Lesion microarray data (GSE141549) | n = 3 functionalis n = 6 full thickness; Microarray data controls: endom n = 42, peritoneum n = 12; n = 9 red, 9 white, 11 black | Peritoneal disease: red, white, black | Healthy controls (functionalis ayer) n = 6 full thickness without reproductive disorders; normal peritoneum | N/A | None | Proliferative, secretory; Microarray samples: Control Endo 17PE, 25SE; Perit 4PE, 8SE; Lesions: Red 2PE, 7 SE; White 5PE, 4SE; Black 6PE, 5 SE | Peritoneal lesions upregulated markers of PE (SOX9+ and pre‐ciliated) versus peritoneum and Upregulated markers for SOX9+LGR5+ subset (WNT7A, KRT17) as in PE. In contrast, secretory cell PAEP and SCGB2A2 and ciliated cell PIFO, TP73 epithelial markers, are ~ to peritoneum. Conclusion: Dysfunctional epithelium is a major driver of endometrial disease with two SOX9 populations dominant in endometriosis. |
| Shih 2022 | Menstrual endometrium | 43 054 | scRNAseq (10X) | n = 33 subjects (n = 11 Dx, n = 13 sx, n = 9 controls) | N/A; another group with Sx but no Dx. | No endometriosis diagnosis. ? Other GYN disorders | White: 10 Dx, 13 sx, 7 controls Black: 0 Dx, 0 sx, 1 control Hispanic: 0 Dx, 0 sx, 0 cont Mixed: 0 Dx, 0 sx, 1 control Other: 1 Dx, 0 sx, 0 control | None on hormones, except 1 case used vaginal P4. Re‐analysis showed no impact on results | Menstrual (heaviest flow, mostly CD 1 or 2) | In cases, menstrual endometrial stromal cells displayed decreased decidualization markers. Menstrual endometrium displayed a marked reduction of uNK cells and enrichment of B cells. Subjects with symptoms but no diagnosis were similar to controls. Conclusion: menstrual endometrium reflects SE abnormalities in endometriosis and could be used for biomarker development. |
| Tan 2022 | Endometrium, endometriosis lesions | 122 000 | scRNAseq (10X) IMC organoids | n = 27 subjects (n = 19 cases, n = 8 controls; n = 14 sequenced | ASRM Stages II‐IV, peritoneal lesions, ovarian "lesions", organoids | No endometriosis or inflammatory conditions | White: 9 cases, 3 controls; Asian: 4 cases, 2 controls; Hisp: 5 cases, 3 controls; Black: 1 case, 0 controls | Progestin [NETA, LVN, drospirenone, norelgestromin] ± ethinyl E2, provera, levonorgestrel IUD, copper IUD | wkly PE: 3 cases, 2 control; inactive 3 cases, 0 control; mens: 1 case, 0 control, exog hormone effect: 7 cases, 7 control PE: 0 cases, 2 controls IE: 0 cases, 1 control ESE: 4 cases, 0 control N/A: 1 case, 1 control | Peritoneal lesions: similar cell composition as EuE; dysregulated innate immune and vascular systems; Immune tolerant peritoneal niche involving Mϕ, DCs; unique perivascular mural cell type with angiogenic and immune cell trafficking properties; novel epithelial progenitor. Ovarian lesions: distinct cell compositions, transcriptomes. Conclusion: immune and vascular components of peritoneal endometriosis favor neo‐angiogenesis and an immune tolerant niche in the peritoneal cavity. |
| Fonseca 2023 | Endometrium, endometriosis lesions, unaffected ovary, and peritoneum | 373 851 | digital scRNAseq | n = 21 subjects n = 17 cases, n = 4 controls n‐54 specimens collected | Cases: n = 17 Endometrium Endometrioma Superficial and deep disease n = 9 w/o GYN disorders; n = 8 w/ adenomyosis, uterine fibroids ± polyp | Controls n = 4 n = 3 PMP, 1 peri‐ menopause, all no evidence of endometriosis, all w/ leiomyoma ± adenomyosis ± uterine polyp | White: 13 cases, 2 controls Black: 2 cases, 0 controls Asian: 1 case, 0 control Other: 1 case, 0 control | Cases: n = 14 on no hormones. n = 1 w/ vaginal ring E+P; n = 1 on E/T, P4; n = 1 on E2+P4. Controls: 3 of 4 on E ± P4; NETA; n = 1 peri‐menopause in luteal phase | Cases: Proliferative phase: n = 7; secretory phase: n = 9; N/A (on hormones) n = 3. Controls: Proliferative n = 0, Secretory n = 1, N/A (on hormones) n = 3 | Cell/molecular signatures of endometrial‐type epithelium and stroma differed across tissues c/w restructuring/transcriptional reprogramming in lesions. Eu E enriched in eEC, endothelium; endometriomas: enriched in B cells and plasma cells, lesions: in mast cells, T/NK‐T cells. Endometriomas: immune and C activation, some cells found only in pts on hormones. ARID1A mutation: pro‐(lymph)angiogenic, stroma/adjacent mesothelium pro‐inflammatory. Lesion ciliated epithelial signatures c/w ovarian cancer. Some histology‐negative mesothelial cells had disease signatures. Conclusion: scRNAseq gives insight into endometriosis phenotypes and depends on hormone status and could identify occult disease. |
| Huang 2023 | Endometrium | 128 243 | scRNAseq (10X) | n = 10 sequenced n = 6 cases, n = 4 controls | ASRM Stages I, II | No endometriosis, benign ovarian cysts | N/A | None | EPE: 3 cases, 3 controls MSE: 3 cases, 3 controls LSE: 1 control | In MSE (WOI) of Stage I/II subjects, one epithelial cell cluster expressing PAEP and CXL14 was absent vs controls; Immune cells in controls decreased in SE, but no cycle variation of total, uNK, and T cells in cases was observed. Pro‐inflammatory cytokine expression was higher in endometrial immune cells in cases. Conclusion: Stage I/II disease is associated with lower epithelial receptivity markers, abnormal immune cell frequencies, and pro‐inflammatory WOI environment. |
Abbreviations: ASRM, American Society for Reproductive Medicine; C, complement; CD, cycle day; c/w, consistent with; DC, dendritic cells; Dx, diagnosis; E2, estradiol; E, estrogen; eEC, endometrial epithelial; exog, exogenous; ECM, extracellular matrix; ESE, early secretory endometrium phase; EuE, eutopic endometrium; FB, fibroblast; FGF, fibroblast growth factor; IE, interval endometrium; IL, interleukin; IUD, intrauterine device; LSE, late secretory phase endometrium; LVN, levonorgestrel; mens, menstrual; Mϕ, macrophages; MAPK, mitogen activated protein kinase; MSE, mid‐secretory endometrium phase; N/A, not available; NETA, norethindrone acetate; P4, progesterone; PAEP, progesterone‐associated endometrial protein; PE, proliferative endometrium phase; sc, single cell; sn, single nuclei; sx, symptoms; RNA, ribonucleic acid; SE, secretory endometrium phase; seq, sequencing; StAR, steroidogenic acute regulatory protein; T, testosterone; TNF, tumor necrosis factor; uNK, uterine natural killer.