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A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium.

ABSTRACT: Endometriosis is an estrogen-dependent inflammatory disorder characterized by the presence of endometrial tissue outside the uterine cavity. Patients experience chronic pelvic pain and infertility, with the most likely origin of the tissue deposits (lesions) being endometrial fragments shed at menses. Menstruation is an inflammatory process associated with a dramatic increase in inflammatory mediators and tissue-resident immune cells. In the present study, we developed and validated a mouse model of endometriosis using syngeneic menstrual endometrial tissue introduced into the peritoneum of immunocompetent mice. We demonstrate the establishment of endometriotic lesions that exhibit similarities to those recovered from patients undergoing laparoscopy. Specifically, in both cases, lesions had epithelial (cytokeratin(+)) and stromal (vimentin/CD10(+)) cell compartments with a well-developed vasculature (CD31(+) endothelial cells). Expression of estrogen receptor ? was increased in lesions compared with the peritoneum or eutopic endometrium. By performing experiments using mice with green fluorescent protein-labeled macrophages (MacGreen) in reciprocal transfers with wild-type mice, we obtained evidence that macrophages present in the peritoneum and in menses endometrium can contribute to the inflammatory microenvironment of the lesions. In summary, we developed a mouse model of endometriosis that exhibits similarities to human peritoneal lesions with respect to estrogen receptor expression, inflammation, and macrophage infiltration, providing an opportunity for further studies and the possible identification of novel therapies for this perplexing disorder.

SUBMITTER: Greaves E

PROVIDER: S-EPMC4076466 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium.

Greaves Erin E Cousins Fiona L FL Murray Alison A Esnal-Zufiaurre Arantza A Fassbender Amelie A Horne Andrew W AW Saunders Philippa T K PT

The American journal of pathology 20140605 7

Endometriosis is an estrogen-dependent inflammatory disorder characterized by the presence of endometrial tissue outside the uterine cavity. Patients experience chronic pelvic pain and infertility, with the most likely origin of the tissue deposits (lesions) being endometrial fragments shed at menses. Menstruation is an inflammatory process associated with a dramatic increase in inflammatory mediators and tissue-resident immune cells. In the present study, we developed and validated a mouse mode ...[more]

PMID: 24910298

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Project description:Study questionIs it possible to establish a genetically engineered mouse model (GEMM) of endometriosis that mimics the natural spread of invasive endometrium?Summary answerEndometriosis occurs in an ARID1A (AT-rich interactive domain-containing protein 1A) and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutant GEMM of endometrial dysfunction following salpingectomy.What is known alreadyAlthough mouse models of endometriosis have long been established, most models rely on intraperitoneal injection of uterine fragments, steroid hormone treatments or the use of immune-compromised mice.Study design, size, durationMice harboring the lactotransferrin-Cre (LtfCre0/+), Arid1afl, (Gt)R26Pik3ca*H1047R and (Gt)R26mTmG alleles were subject to unilateral salpingectomies at 6 weeks of age. Control (n = 9), LtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/+ (n = 8) and LtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/fl (n = 9) were used for the study. The (Gt)R26mTmG allele was used for the purpose of fluorescent lineage tracing of endometrial epithelium. LtfCre0/+; (Gt)R26mTmG (n = 3) and LtfCre0/+; (Gt)R26Pik3ca*H1047R/mTmG; Arid1afl/fl (n = 4) were used for this purpose. Mice were followed until the endpoint of vaginal bleeding at an average time of 17 weeks of age.Participants/materials, setting, methodsAt 6 weeks of age, mice were subjected to salpingectomy surgery. Mice were followed until the time point of vaginal bleeding (average 17 weeks), or aged for 1 year in the case of control mice. At time of sacrifice, endometriotic lesions, ovaries and uterus were collected for the purpose of histochemical and immunohistochemical analyses. Samples were analyzed for markers of the endometriotic tissue and other relevant biomarkers.Main results and the role of chanceFollowing salpingectomy, LtfCre0/+; (Gt)R26Pik3ca*H1047R/mTmG; Arid1afl/fl mice developed endometriotic lesions, including lesions on the ovary, omentum and abdominal wall. Epithelial glands within lesions were negative for ARID1A and positive for phospho-S6 staining, indicating ARID1A-PIK3CA co-mutation status, and expressed EGFP (enhanced green fluorescent protein), indicating endometrial origins.Large-scale dataN/A.Limitations, reasons for cautionLtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/fl mice develop vaginal bleeding as a result of endometrial dysfunction at an average age of 17 weeks and must be sacrificed. Furthermore, while this model mimics the natural spread of endometriotic tissue directly from the uterus to the peritoneum, the data presented do not reject current hypotheses on endometriosis pathogenesis.Wider implications of the findingsThe idea that endometriosis is the result of abnormal endometrial tissue colonizing the peritoneum via retrograde menstruation has gained widespread support over the past century. However, most models of endometriosis take for granted this possibility, relying on the surgical removal of bulk uterine tissue and subsequent transplantation into the peritoneum. Growing evidence suggests that somatic mutations in ARID1A and PIK3CA are present in the endometrial epithelium. The establishment of a GEMM which mimics the natural spread of endometrium and subsequent lesion formation supports the hypothesis that endometriosis is derived from mutant endometrial epithelium with invasive properties.Study funding/competing interest(s)This research was supported by the American Cancer Society PF-17-163-02-DDC (M.R.W.), the Mary Kay Foundation 026-16 (R.L.C.) and the Ovarian Cancer Research Fund Alliance 457446 (R.L.C.). The authors declare no competing interests.

Project description:BackgroundEndometriosis is a chronic, estrogen-dependent disorder where inflammation contributes to disease-associated symptoms of pelvic pain and infertility. Immune dysfunction includes insufficient immune lesion clearance, a pro-inflammatory endometrial environment, and systemic inflammation. Comprehensive understanding of endometriosis immune pathophysiology in different hormonal milieu and disease severity has been hampered by limited direct characterization of immune populations in endometrium, blood, and lesions. Simultaneous deep phenotyping at single-cell resolution of complex tissues has transformed our understanding of the immune system and its role in many diseases. Herein, we report mass cytometry and high dimensional analyses to study immune cell phenotypes, abundance, activation states, and functions in endometrium and blood of women with and without endometriosis in different cycle phases and disease stages.MethodsA case-control study was designed. Endometrial biopsies and blood (n = 60 total) were obtained from women with (n = 20, n = 17, respectively) and without (n = 14, n = 9) endometriosis in the proliferative and secretory cycle phases of the menstrual cycle. Two mass cytometry panels were designed: one broad panel and one specific for mononuclear phagocytic cells (MPC), and all samples were multiplexed to characterize both endometrium and blood immune composition at unprecedented resolution. We combined supervised and unsupervised analyses to finely define the immune cell subsets with an emphasis on MPC. Then, association between cell types, protein expression, disease status, and cycle phase were performed.ResultsThe broad panel highlighted a significant modification of MPC in endometriosis; thus, they were studied in detail with an MPC-focused panel. Endometrial CD91+ macrophages overexpressed SIRPα (phagocytosis inhibitor) and CD64 (associated with inflammation) in endometriosis, and they were more abundant in mild versus severe disease. In blood, classical and intermediate monocytes were less abundant in endometriosis, whereas plasmacytoid dendritic cells and non-classical monocytes were more abundant. Non-classical monocytes were higher in severe versus mild disease.ConclusionsA greater inflammatory phenotype and decreased phagocytic capacity of endometrial macrophages in endometriosis are consistent with defective clearance of endometrial cells shed during menses and in tissue homeostasis, with implications in endometriosis pathogenesis and pathophysiology. Different proportions of monocytes and plasmacytoid dendritic cells in blood from endometriosis suggest systemically aberrant functionality of the myeloid system opening new venues for the study of biomarkers and therapies for endometriosis.

Dataset Information

A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium.

Publications

A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium.

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