Oestrogen, progesterone and stem cells: the discordant trio in endometriosis?

Published online by Cambridge University Press: 08 March 2018 Oestrogen–progesterone signalling is highly versatile and critical for the maintenance of healthy endometrium in humans. The genomic and nongenomic signalling cascades initiated by these hormones in differentiated cells of endometrium have been the primary focus of research since 1920s. However, last decade of research has shown a significant role of stem cells in the maintenance of a healthy endometrium and the modulatory effects of hormones on these cells. Endometriosis, the growth of endometrium outside the uterus, is very common in infertile patients and the elusiveness in understanding of disease pathology causes hindrance in selection of treatment approaches to enhance fertility. In endometriosis, the stem cells are dysfunctional as it can confer progesterone resistance to their progenies resulting in disharmony of hormonal orchestration of endometrial homeostasis. The bidirectional communication between stem cell signalling pathways and oestrogen–progesterone signalling is found to be disrupted in endometriosis though it is not clear which precedes the other. In this paper, we review the intricate connection between hormones, stem cells and the cross-talks in their signalling cascades in normal endometrium and discuss how this is deregulated in endometriosis. Re-examination of the oestrogen–progesterone dependency of endometrium with a focus on stem cells is imperative to delineate infertility associated with endometriosis and thereby aid in designing better treatment modalities. - Type - Review - Information - Copyright - Copyright © Cambridge University Press 2018 1. Beato, M. and Klug, J. (2000) Steroid hormone receptors: an update. Human Reproduction Update 6, 225-236 CrossRefGoogle ScholarPubMed 2. Groothuis, P.G. et al. (2007) Estrogen and the endometrium: lessons learned from gene expression profiling in rodents and human. Human Reproduction Update 13, 405-417 CrossRefGoogle ScholarPubMed 3. Hapangama, D.K. et al. (2015) Estrogen receptor β: the guardian of the endometrium. Human Reproduction Update 21, 174-193 CrossRefGoogle ScholarPubMed 4. Young, S.L. and Lessey, B.A. (2010) Progesterone function in human endometrium: clinical perspectives. Seminars in Reproductive Medicine 28, 5-16 CrossRefGoogle ScholarPubMed 5. Maybin, J.A. and Critchley, H.O.D. (2015) Menstrual physiology: implications for endometrial pathology and beyond. Human Reproduction Update 21, 748-761 CrossRefGoogle ScholarPubMed 6. Figueira, P.G.M. et al. (2011) Stem cells in endometrium and their role in the pathogenesis of endometriosis. Annals of the New York Academy of Sciences 1221, 10-17 CrossRefGoogle ScholarPubMed 7. Mote, P.A. et al. (1999) Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle. The Journal of Clinical Endocrinology and Metabolism 84, 2963-2971 Google Scholar 8. Arnett-Mansfield, R.L. et al. (2001) Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium. Cancer Research 61, 4576-4582 Google Scholar 9. Mylonas, I. et al. (2007) Steroid receptors ERalpha, ERbeta, PR-A and PR-B are differentially expressed in normal and atrophic human endometrium. Histology and Histopathology 22, 169-176 Google Scholar 10. Gorodeski, I.G. et al. (1986) Effect of progesterone injection on progesterone receptor levels and distribution in untreated and short-term Premarin-primed pre-menopausal and post-menopausal endometrium. Maturitas 8, 353-358 CrossRefGoogle ScholarPubMed 11. Whitehead, M.I. et al. (1981) Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. The New England journal of Medicine 305, 1599-1605 Google Scholar 12. Gargett, C.E. et al. (2015) Endometrial stem/progenitor cells: the first 10 years. Human Reproduction Update 22, 137-63Google Scholar 13. Mutlu, L. et al. (2015) The endometrium as a source of mesenchymal stem cells for regenerative medicine. Biology of Reproduction 92, 138 Google Scholar 14. Masuda, H. et al. (2015) Endometrial side population cells: potential adult stem/progenitor cells in endometrium. Biology of Reproduction 93, 84-84 Google Scholar 15. Masuda, H. et al. (2010) Stem cell-like properties of the endometrial side population: implication in endometrial regeneration. PLoS One 5, e10387 Google Scholar 16. Padykula, H.A. (1991) Regeneration in the primate uterus: the role of stem cells. Annals of the New York Academy of Sciences 622, 47-56 Google Scholar 17. Gargett, C.E. and Ye, L. (2012) Endometrial reconstruction from stem cells. Fertility and Sterility 98, 11-20 Google Scholar 18. Ulrich, D. et al. (2014) Mesenchymal stem/stromal cells in post-menopausal endometrium. Human Reproduction (Oxford, England) 29, 1895-1905 CrossRefGoogle ScholarPubMed 19. Yang, J. and Huang, F. (2014) Stem cell and endometriosis: new knowledge may be producing novel therapies. International Journal of Clinical and Experimental Medicine 7, 3853-3858 Google Scholar 20. Hufnagel, D. et al. (2015) The role of stem cells in the etiology and pathophysiology of endometriosis. Seminars in Reproductive Medicine 33, 333-340 CrossRefGoogle ScholarPubMed 21. Sampson, J.A. (1927) Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. The American Journal of Pathology 3, 93-110.43Google ScholarPubMed 22. Benagiano, G. et al. (2014) The history of endometriosis. Gynecologic and Obstetric Investigation 78, 1-9 Google Scholar 23. Gruenwald, P. (1942) Origin of endometriosis from the mesenchyme of the celomic walls. American Journal of Obstetrics and Gynecology 44, 470-474 CrossRefGoogle Scholar 24. Gargett, C.E. et al. (2014) Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. Molecular Human Reproduction 20, 591-598 Google Scholar 25. Pittatore, G. et al. (2014) Endometrial adult/progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy. Reproductive Sciences (Thousand Oaks, Calif) 21, 296-304 Google Scholar 26. Heidari-Keshel, S. et al. (2015) Tissue-specific somatic stem-cell isolation and characterization from human endometriosis. Key roles in the initiation of endometrial proliferative disorders. Minerva Medica 106, 95-108 Google Scholar 27. Bulun, S. et al. (2015) Molecular biology of endometriosis: from aromatase to genomic abnormalities. Seminars in Reproductive Medicine 33, 220-224 Google ScholarPubMed 28. Al-Sabbagh, M. et al. (2012) Mechanisms of endometrial progesterone resistance. Molecular and Cellular Endocrinology 358, 208-215 CrossRefGoogle ScholarPubMed 29. Clevers, H. et al. (2014) An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science 346, 1248012-1248012 Google Scholar 30. Artavanis-Tsakonas, S. et al. (1999) Notch signaling: cell fate control and signal integration in development. Science (New York, NY) 284, 770-776 Google Scholar 31. Briscoe, J. and Thérond, P.P. (2013) The mechanisms of Hedgehog signalling and its roles in development and disease. Nature Reviews Molecular Cell Biology 14, 418-431 CrossRefGoogle ScholarPubMed 32. Hong, S.H. et al. (2004) Expression of estrogen receptor-alpha and -beta, glucocorticoid receptor, and progesterone receptor genes in human embryonic stem cells and embryoid bodies. Molecules and Cells 18, 320-325 CrossRefGoogle ScholarPubMed 33. Carroll, K.J. et al. (2014) Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche. Developmental Cell 29, 437-453 Google Scholar 34. Brannvall, K. (2002) Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation. Molecular and Cellular Neuroscience 21, 512-520 CrossRefGoogle ScholarPubMed 35. Gallego, M.J. et al. (2009) Opioid and progesterone signaling is obligatory for early human embryogenesis. Stem Cells and Development 18, 737-740 Google Scholar 36. Gallego, M.J. et al. (2010) The pregnancy hormones human chorionic gonadotropin and progesterone induce human embryonic stem cell proliferation and differentiation into neuroectodermal rosettes. Stem Cell Research & Therapy 1, 28 Google Scholar 37. López-González, R. et al. (2011) Progesterone and 17β-estradiol increase differentiation of mouse embryonic stem cells to motor neurons. IUBMB Life 63, 930-939 Google Scholar 38. Kang, H.Y. et al. (2016) Inhibitory effect of progesterone during early embryonic development: suppression of myocardial differentiation and calcium-related transcriptome by progesterone in mESCs. Reproductive Toxicology 64, 169-179 Google Scholar 39. Visvader, J.E. and Stingl, J. (2014) Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes & Development 28, 1143-1158 Google Scholar 40. Joshi, P.A. et al. (2010) Progesterone induces adult mammary stem cell expansion. Nature 465, 803-807 Google Scholar 41. Illing, A. et al. (2012) Estradiol increases hematopoietic stem and progenitor cells independent of its actions on bone. Haematologica 97, 1131-1135 Google Scholar 42. Marin-Husstege, M. et al. (2004) Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Developmental Neuroscience 26, 245-254 CrossRefGoogle ScholarPubMed 43. Gao, Y. et al. (2013) Crosstalk between Wnt/β-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells. PLoS ONE 8, e82436 CrossRefGoogle ScholarPubMed 44. Wang, X. et al. (2012) Progesterone promotes neuronal differentiation of human umbilical cord mesenchymal stem cells in culture conditions that mimic the brain microenvironment. Neural Regeneration Research 7, 1925-1930 Google ScholarPubMed 45. Moslehi, A. et al. (2016) The effect of progesterone and 17-β estradiol on membrane-bound HLA-G in adipose derived stem cells. The Korean Journal of Physiology & Pharmacology 20, 341 Google Scholar 46. Kyurkchiev, D.S. et al. (2011) Effect of progesterone on human mesenchymal stem cells. Vitamins and Hormones 87, 217-237 CrossRefGoogle ScholarPubMed 47. Schwab, K.E. and Gargett, C.E. (2007) Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Human Reproduction 22, 2903-2911 CrossRefGoogle ScholarPubMed 48. Masuda, H. et al. (2012) A novel marker of human endometrial mesenchymal stem-like cells. Cell Transplantation 21, 2201-2214 Google Scholar 49. Cervelló, I. et al. (2011) Reconstruction of endometrium from human endometrial side population cell lines. PLoS ONE 6, e21221 Google Scholar 50. Gil-Sanchis, C. et al. (2013) Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) as a putative human endometrial stem cell marker. Molecular Human Reproduction 19, 407-414 Google Scholar 51. Valentijn, A.J. et al. (2013) SSEA-1 isolates human endometrial basal glandular epithelial cells: phenotypic and functional characterization and implications in the pathogenesis of endometriosis. Human Reproduction 28, 2695-2708 Google Scholar 52. Nguyen, H.P.T. et al. (2017) N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays. Human Reproduction 425, 1-15 Google Scholar 53. Nguyen, H.P.T. et al. (2012) Differential expression of Wnt signaling molecules between pre- and postmenopausal endometrial epithelial cells suggests a population of putative epithelial stem/progenitor cells reside in the basalis layer. Endocrinology 153, 2870-2883 Google Scholar 54. Gargett, C.E. et al. (2012) Endometrial regeneration and endometrial stem/progenitor cells. Reviews in Endocrine and Metabolic Disorders 13, 235-251 Google Scholar 55. Schwab, K.E. et al. (2005) Putative stem cell activity of human endometrial epithelial and stromal cells during the menstrual cycle. Fertility and Sterility 84, 1124-1130 Google Scholar 56. Janzen, D.M. et al. (2013) Estrogen and progesterone together expand murine endometrial epithelial progenitor cells. Stem Cells (Dayton, OH) 31, 808-822 CrossRefGoogle ScholarPubMed 57. Cervelló, I. et al. (2010) Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PloS One 5, e10964 CrossRefGoogle ScholarPubMed 58. Chan, R.W.S. et al. (2012) Role of label-retaining cells in estrogen-induced endometrial regeneration. Reproductive Sciences (Thousand Oaks, CA) 19, 102-114 CrossRefGoogle ScholarPubMed 59. Hyodo, S. et al. (2011) Endometrial injury increases side population cells in the uterine endometrium: a decisive role of estrogen. The Tohoku Journal of Experimental Medicine 224, 47-55 CrossRefGoogle ScholarPubMed 60. Gunjal, P. et al. (2015) Very small embryonic-like stem cells are the elusive mouse endometrial stem cells- a pilot study. Journal of Ovarian Research 8, 9 Google Scholar 61. Bhartiya, D. et al. (2013) Neonatal exposure to estrogen affects very small ES-like stem cells (VSELs) leading to various pathologies in adults including cancer. Journal of Cancer Stem Cell Research 1, 1 Google Scholar 62. Taylor, H.S. (2004) Endometrial cells derived from donor stem cells in bone marrow transplant recipients. The Journal of the American Medical Association 292, 81 Google Scholar 63. Aghajanova, L. et al. (2010) The bone marrow-derived human mesenchymal stem cell: potential progenitor of the endometrial stromal fibroblast. Biology of Reproduction 82, 1076-1087 CrossRefGoogle ScholarPubMed 64. Mints, M. et al. (2007) Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient. Human Reproduction 23, 139-143 Google Scholar 65. Foresta, C. et al. (2010) Role of estrogen receptors in menstrual cycle-related neoangiogenesis and their influence on endothelial progenitor cell physiology. Fertility and Sterility 93, 220-228 Google Scholar 66. Hamada, H. et al. (2006) Estrogen receptors alpha and beta mediate contribution of bone marrow-derived endothelial progenitor cells to functional recovery after myocardial infarction. Circulation 114, 2261-2270 Google Scholar 67. Matsubara, Y. and Matsubara, K. (2012) Estrogen and progesterone play pivotal roles in endothelial progenitor cell proliferation. Reproductive Biology and Endocrinology 10, 2 Google Scholar 68. Iwakura, A. et al. (2006) Estradiol enhances recovery after myocardial infarction by augmenting incorporation of bone marrow-derived endothelial progenitor cells into sites of ischemia-induced neovascularization via endothelial nitric oxide synthase-mediated activation of matrix m. Circulation 113, 1605-1614 CrossRefGoogle Scholar 69. Heissig, B. et al. (2002) Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625-637 Google Scholar 70. Fadini, G.P. et al. (2008) Gender differences in endothelial progenitor cells and cardiovascular risk profile. Arteriosclerosis, Thrombosis, and Vascular Biology 28 Google Scholar 71. Sugawara, J. et al. (2005) Circulating endothelial progenitor cells during human pregnancy. The Journal of Clinical Endocrinology & Metabolism 90, 1845-1848 Google Scholar 72. Robb, A.O. et al. (2008) Influence of menstrual cycle on circulating endothelial progenitor cells. Human Reproduction 24, 619-625 Google Scholar 73. Spitzer, T.L.B. et al. (2012) Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype. Biology of Reproduction 86, 58 Google Scholar 74. Wang, Y. et al. (2010) Wnt/Β-catenin and sex hormone signaling in endometrial homeostasis and cancer. Oncotarget 1, 674-684 Google Scholar 75. Fan, X. et al. (2012) Dynamic regulation of Wnt7a expression in the primate endometrium: implications for postmenstrual regeneration and secretory transformation. Endocrinology 153, 1063-1069 Google Scholar 76. Yu, W.-Z. et al. (2015) Role of Wnt5a in the differentiation of human embryonic stem cells into endometrium-like cells. International Journal of Clinical and Experimental Pathology 8, 5478-5484 Google Scholar 77. Bukowska, J. et al. (2015) The importance of the canonical Wnt signaling pathway in the porcine endometrial stromal stem/progenitor cells: implications for regeneration. Stem Cells and Development 24, 2873-2885 Google Scholar 78. Kouzmenko, A.P. et al. (2004) Wnt/beta-catenin and estrogen signaling converge in vivo. The Journal of Biological Chemistry 279, 40255-40258 Google Scholar 79. Shi, B. et al. (2007) Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Molecular and Cellular Biology 27, 5105-5119 Google Scholar 80. Chandar, N. et al. (2005) P53 and beta-catenin activity during estrogen treatment of osteoblasts. Cancer Cell International 5, 24 Google Scholar 81. Wang, Y. et al. (2009) Progesterone inhibition of Wnt/beta-catenin signaling in normal endometrium and endometrial cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 15, 5784-5793 Google Scholar 82. Hou, X. et al. (2004) Canonical Wnt signaling is critical to estrogen-mediated uterine growth. Molecular Endocrinology (Baltimore, MD) 18, 3035-3049 Google Scholar 83. Abu-Jawdeh, G. et al. (1999) Differential expression of frpHE: a novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy. Laboratory Investigation, A Journal of Technical Methods and Pathology 79, 439-447 Google Scholar 84. Wang, K. et al. (2008) Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism. The Journal of Biological Chemistry 283, 23371-23375 CrossRefGoogle ScholarPubMed 85. Essers, M.A.G. et al. (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science (New York, NY) 308, 1181-1184 Google Scholar 86. Ruiz i Altaba, A. et al. (2002) Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Reviews Cancer 2, 361-372 Google Scholar 87. Migone, F.F. et al. (2012) Dominant activation of the hedgehog signaling pathway alters development of the female reproductive tract. Genesis (New York, NY: 2000) 50, 28-40 CrossRefGoogle ScholarPubMed 88. Franco, H.L. et al. (2010) Constitutive activation of smoothened leads to female infertility and altered uterine differentiation in the mouse. Biology of Reproduction 82, 991-999 Google Scholar 89. Kim, K.H. et al. (2009) Expression of sonic hedgehog signaling molecules in normal, hyperplastic and carcinomatous endometrium. Pathology International 59, 279-287 CrossRefGoogle ScholarPubMed 90. Franco, H.L. et al. (2010) Ablation of Indian hedgehog in the murine uterus results in decreased cell cycle progression, aberrant epidermal growth factor signaling, and increased estrogen signaling. Biology of Reproduction 82, 783-790 Google Scholar 91. Pu, Y. et al. (2004) Sonic hedgehog-patched Gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching. Developmental Biology 273, 257-275 CrossRefGoogle ScholarPubMed 92. Matsumoto, H. et al. (2002) Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus. Developmental Biology 245, 280-290 Google Scholar 93. Simon, L. et al. (2009) Stromal progesterone receptors mediate induction of Indian Hedgehog (IHH) in uterine epithelium and its downstream targets in uterine stroma. Endocrinology 150, 3871-3876 Google Scholar 94. Takamoto, N. et al. (2002) Identification of Indian hedgehog as a progesterone-responsive gene in the murine uterus. Molecular Endocrinology (Baltimore, MD) 16, 2338-2348 Google Scholar 95. Wei, Q. et al. (2010) Indian Hedgehog and its targets in human endometrium: menstrual cycle expression and response to CDB-2914. The Journal of Clinical Endocrinology and Metabolism 95, 5330-5337 Google Scholar 96. Koga, K. et al. (2008) Novel link between estrogen receptor {alpha} and hedgehog pathway in breast cancer. Anticancer Research 28, 731-739 Google Scholar 97. Kameda, C. et al. (2010) Oestrogen receptor-alpha contributes to the regulation of the hedgehog signalling pathway in ERalpha-positive gastric cancer. British Journal of Cancer 102, 738-747 Google Scholar 98. Kurihara, I. et al. (2007) COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genetics 3, e102 Google Scholar 99. Liu, J. et al. (2010) Notch signaling in the regulation of stem cell self-renewal and differentiation. Current topics in Developmental Biology 92, 367-409 CrossRefGoogle ScholarPubMed 100. Su, R.-W. et al. (2016) Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility. Proceedings of the National Academy of Sciences of the United States of America 113, 2300-2305 Google Scholar 101. Mikhailik, A. et al. (2009) Notch ligand-dependent gene expression in human endometrial stromal cells. Biochemical and Biophysical Research Communications 388, 479-482 Google Scholar 102. Murakami, K. et al. (2014) Decidualization induces a secretome switch in perivascular niche cells of the human endometrium. Endocrinology 155, 4542-4553 CrossRefGoogle ScholarPubMed 103. Cobellis, L. et al. (2008) The pattern of expression of Notch protein members in normal and pathological endometrium. Journal of Anatomy 213, 464-472 CrossRefGoogle ScholarPubMed 104. Suzuki, T. et al. (2000) Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers. International Journal of Oncology 17, 1131-1139 Google ScholarPubMed 105. Van Sinderen, M. et al. (2014) Localisation of the Notch family in the human endometrium of fertile and infertile women. Journal of Molecular Histology 45, 697-706 Google Scholar 106. Mazella, J. et al. (2008) Expression of Delta-like protein 4 in the human endometrium. Endocrinology 149, 15-19 Google Scholar 107. Rizzo, P. et al. (2008) Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Research 68, 5226-5235 Google Scholar 108. Soares, R. et al. (2004) Evidence for the notch signaling pathway on the role of estrogen in angiogenesis. Molecular Endocrinology (Baltimore, MD) 18, 2333-2343 CrossRefGoogle ScholarPubMed 109. Lydon, J.P. and Edwards, D.P. (2009) Finally! A model for progesterone receptor action in normal human breast. Endocrinology 150, 2988-2990 Google Scholar 110. Afshar, Y. et al. (2012) Notch1 is regulated by chorionic gonadotropin and progesterone in endometrial stromal cells and modulates decidualization in primates. Endocrinology 153, 2884-2896 Google Scholar 111. Wei, Y. et al. (2012) Nuclear estrogen receptor-mediated Notch signaling and GPR30-mediated PI3K/AKT signaling in the regulation of endometrial cancer cell proliferation. Oncology Reports 27, 504-510 Google Scholar 112. Hao, L. et al. (2010) Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells. Oncogene 29, 201-213 Google Scholar 113. Bulun, S.E. et al. (2010) Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Seminars in Reproductive Medicine 28, 36-43 Google Scholar 114. Macer, M.L. and Taylor, H.S. (2012) Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstetrics and Gynecology clinics of North America 39, 535-549 Google Scholar 115. Forte, A. et al. (2014) Genetic, epigenetic and stem cell alterations in endometriosis: new insights and potential therapeutic perspectives. Clinical Science (London, England: 1979) 126, 123-138 CrossRefGoogle ScholarPubMed 116. Du, H. and Taylor, H.S. (2007) Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells 25, 2082-2086 Google Scholar 117. Pluchino, N. and Taylor, H.S. (2016) Endometriosis and stem cell trafficking. Reproductive Sciences 23, 1616-1619 Google Scholar 118. Laschke, M.W. et al. (2011) Endothelial progenitor cells contribute to the vascularization of endometriotic lesions. The American Journal of Pathology 178, 442-450 Google Scholar 119. Proestlingm, K. et al. (2016) Enhanced expression of the stemness-related factors OCT4, SOX15 and TWIST1 in ectopic endometrium of endometriosis patients. Reproductive Biology and Endocrinology: RB&E 14, 81 CrossRefGoogle Scholar 120. Götte, M. et al. (2008) Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma. The Journal of Pathology 215, 317-329 Google Scholar 121. Forte, A. et al. (2009) Expression pattern of stemness-related genes in human endometrial and endometriotic tissues. 15, 392-401 Google ScholarPubMed 122. Kao, A. et al. (2011) Comparative study of human eutopic and ectopic endometrial mesenchymal stem cells and the development of an in vivo endometriotic invasion model. Fertility and Sterility 95, 1308-1315.e1 CrossRefGoogle Scholar 123. Santamaria, X. et al. (2012) Migration of cells from experimental endometriosis to the uterine endometrium. Endocrinology 153, 5566-5574 Google Scholar 124. Djokovic, D. and Calhaz-Jorge, C. (2014) Somatic stem cells and their dysfunction in endometriosis. Frontiers in Surgery 1, 51 Google Scholar 125. Barragan, F. et al. (2016) Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis. Biology of Reproduction 94, 118, 1-20CrossRefGoogle ScholarPubMed 126. Yu, W. et al. (2015) Co-culture with endometrial stromal cells enhances the differentiation of human embryonic stem cells into endometrium-like cells. Experimental and Therapeutic Medicine 10, 43-50 Google Scholar 127. Chen, Y. et al. (2014) Increased expression of the adult stem cell marker Musashi-1 in the ectopic endometrium of adenomyosis does not correlate with serum estradiol and progesterone levels. European Journal of Obstetrics, Gynecology, and Reproductive Biology 173, 88-93 CrossRefGoogle Scholar 128. Sakr, S. et al. (2014) Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment. Endocrinology 155, 1489-1497 Google Scholar 129. Wang, X. et al. (2015) Chemoattraction of bone marrow-derived stem cells towards human endometrial stromal cells is mediated by estradiol regulated CXCL12 and CXCR4 expression. Stem Cell Research 15, 14-22 Google Scholar 130. Ersoy, G.S. et al. (2016) Medical Therapies for Endometriosis Differentially Inhibit Stem Cell Recruitment. Reproductive Sciences 24, 818-823 Google Scholar 131. Rudzitis-Auth, J. et al. (2016) Estrogen stimulates homing of endothelial progenitor cells to endometriotic lesions. The American Journal of Pathology 186, 2129-2142 Google Scholar 132. Thiruchelvam, U. et al. (2016) Increased uNK progenitor cells in women with endometriosis and infertility are associated with low levels of endometrial stem cell factor. American Journal of Reproductive Immunology (New York, NY: 1989) 75, 493-502 Google Scholar 133. Zhang, H. et al. (2015) Metformin regulates stromal-epithelial cells communication via Wnt2/β-catenin signaling in endometriosis. Molecular and Cellular Endocrinology 413, 61-65 Google Scholar 134. Matsuzaki, S. and Darcha, C. (2013) In vitro effects of a small-molecule antagonist of the Tcf/ß-Catenin complex on endometrial and endometriotic cells of patients with endometriosis. PLoS ONE 8, e61690 CrossRefGoogle ScholarPubMed 135. Gaetje, R. et al. (2007) Characterization of WNT7A expression in human endometrium and endometriotic lesions. Fertility and Sterility 88, 1534-1540 Google Scholar 136. Xiong, W. et al. (2016) Hypoxia promotes invasion of endometrial stromal cells via hypoxia-inducible factor 1α upregulation-mediated β-catenin activation in endometriosis. Reproductive Sciences (Thousand Oaks, Calif) 23, 531-541 CrossRefGoogle ScholarPubMed 137. Yu, C.-X. et al. (2014) Correlation of changes of (non)exfoliated endometrial organelles and expressions of Musashi-1 and β-catenin with endometriosis in menstrual period. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology 30, 861-867 Google Scholar 138. Matsuzaki, S. et al. (2014) Targeting the Wnt/β-catenin pathway in endometriosis: a potentially effective approach for treatment and prevention. Molecular and Cellular Therapies 2, 36 Google Scholar 139. Kiewisz, J. et al. (2015) Participation of WNT and β-catenin in physiological and pathological endometrial changes: association with angiogenesis. BioMed Research International 2015, 1-11 CrossRefGoogle ScholarPubMed 140. Brueggmann, D. et al. (2016) Expression of Wnt signaling pathway genes in human endometriosis tissue: a pilot study. European Journal of Obstetrics, Gynecology, and Reproductive Biology 199, 214-215 Google Scholar 141. Brueggmann, D. et al. (2015) Expression of Wnt-signaling pathway genes and Wnt-target genes in human endometriosis tissue [25]. Obstetrics & Gynecology 125, 18S Google Scholar 142. Matsuzaki, S. et al. (2010) Impaired down-regulation of E-cadherin and β-catenin protein expression in endometrial epithelial cells in the Mid-secretory endometrium of infertile patients with endometriosis. The Journal of Clinical Endocrinology & Metabolism 95, 3437-3445 CrossRefGoogle ScholarPubMed 143. Liang, Y. et al. (2016) Expression and significance of WNT4 in ectopic and eutopic endometrium of human endometriosis. Reproductive Sciences (Thousand Oaks, Calif) 23, 379-385 Google Scholar 144. Pabona, J.M.P. et al. (2012) Krüppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis. The Journal of Clinical Endocrinology and Metabolism 97, E376-E392 Google Scholar 145. Zhang, L. et al. (2016) 17 β-Estradiol promotes vascular endothelial growth factor expression via the Wnt/β-catenin pathway during the pathogenesis of endometriosis. Molecular Human Reproduction 22, 526-535 Google Scholar 146. Albertsen, H.M. and Ward, K. (2016) Genes linked to endometriosis by GWAS Are integral to cytoskeleton regulation and suggests that mesothelial barrier homeostasis is a factor in the pathogenesis of endometriosis. Reproductive Sciences. 24, 803-811 Google Scholar 147. Katoh, Y. and Katoh, M. (2008) Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). International Journal of Molecular Medicine 22, 271-275 Google Scholar 148. Heard, M.E. et al. (2015) Kruppel-like factor 13 deficiency in uterine endometrial cells contributes to defective steroid hormone receptor signaling but not lesion establishment in a mouse model of endometriosis. Biology of Reproduction 92, 140 Google Scholar 149. Smith, K. et al. (2011) Endometrial Indian hedgehog expression is decreased in women with endometriosis. Fertility and Sterility 95, 2738-41-3 Google Scholar 150. Burney, R.O. et al. (2007) Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148, 3814-3826 Google Scholar 151. Lin, S.-C. et al. (2014) Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. The Journal of Clinical Endocrinology & Metabolism 99, E427-E437 Google Scholar 152. Zhang, D. et al. (2002) Direct interaction of the Krüppel-like family (KLF) member, BTEB1, and PR mediates progesterone-responsive gene expression in endometrial epithelial cells. Endocrinology 143, 62-73 Google Scholar 153. Pabona, J.M.P. et al. (2009) Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus. The Journal of Endocrinology 200, 63-73 CrossRefGoogle ScholarPubMed 154. Heard, M.E. et al. (2014) Krüppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis. Endocrinology 155, 1532-1546 Google Scholar 155. Vasquez, Y.M. et al. (2016) Endometrial expression of steroidogenic factor 1 promotes cystic glandular morphogenesis. Molecular Endocrinology 30, 518-532 CrossRefGoogle ScholarPubMed 156. Er, T.-K. et al. (2016) Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer. Journal of Molecular Medicine 94, 835-847 Google Scholar 157. He, H. et al. (2016) Lentiviral vector-mediated down-regulation of Notch1 in endometrial stem cells results in proliferation and migration in endometriosis. Molecular and Cellular Endocrinology 434, 210-218 Google Scholar 158. Su, R.-W. et al. (2015) Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization. The Journal of Clinical Endocrinology and Metabolism 100, E433-E442 Google Scholar 159. Wu, Y. et al. (2006) Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics: Official Journal of the DNA Methylation Society 1, 106-111 Google Scholar 160. Kurita, T. et al. (2005) The activation function-1 domain of estrogen receptor α in uterine stromal cells is required for mouse but not human uterine epithelial response to estrogen. Differentiation 73, 313-322 Google Scholar 161. Turco, M.Y. et al. (2017) Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nature Cell Biology 19, 568-577 Google Scholar 162. Boretto, M. et al. (2017) Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development 144, 1775-1786 Google Scholar - 11 - Cited by Cited by Crossref Citations Asghari, Samira Valizadeh, Amir Aghebati-Maleki, Leili Nouri, Mohammad and Yousefi, Mehdi 2018. Endometriosis: Perspective, lights, and shadows of etiology. Biomedicine & Pharmacotherapy, Vol. 106, Issue. , p. 163. Lara, Evelyn Rivera, Nathaly Cabezas, Joel Navarrete, Felipe Saravia, Fernando Rodríguez-Alvarez, Lleretny and Castro, Fidel 2018. Endometrial Stem Cells in Farm Animals: Potential Role in Uterine Physiology and Pathology. Bioengineering, Vol. 5, Issue. 3, p. 75. Filippova, E. S. Mezhlumova, N. A. Gamisoniya, A. M. El'darov, Ch. M. Kuznetsova, M. V. Trofimov, D. Yu. Pavlovich, S. V. Kozachenko, I. F. Bobrov, M. Yu. and Adamyan, L. V. 2019. Profiling of miRNA and mRNA in eutopic and ectopic endometrial tissues in endometrioma. Problemy reproduktsii, Vol. 25, Issue. 2, p. 27. Peng, Fei Cheng, Xiyao Wang, Hongwei Song, Shikui Chen, Tian Li, Xin He, Yijun Huang, Yongqi Liu, Sen Yang, Fei and Su, Zhengding 2019. Structure-based reconstruction of a Mycobacterium hypothetical protein into an active Δ5–3-ketosteroid isomerase. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1867, Issue. 9, p. 821. Zhu, Haiyan Pan, Yibin Jiang, Yinshen Li, Jing Zhang, Yanling and Zhang, Songying 2019. Activation of the Hippo/TAZ pathway is required for menstrual stem cells to suppress myofibroblast and inhibit transforming growth factor β signaling in human endometrial stromal cells. Human Reproduction, Vol. 34, Issue. 4, p. 635. AlAshqar, Abdelrahman Patzkowsky, Kristin Afrin, Sadia Wild, Robert Taylor, Hugh S. and Borahay, Mostafa A. 2019. Cardiometabolic Risk Factors and Benign Gynecologic Disorders. Obstetrical & Gynecological Survey, Vol. 74, Issue. 11, p. 661. Filby, Caitlin E. Rombauts, Luk Montgomery, Grant W. Giudice, Linda C. and Gargett, Caroline E. 2020. Cellular Origins of Endometriosis: Towards Novel Diagnostics and Therapeutics. Seminars in Reproductive Medicine, Vol. 38, Issue. 02/03, p. 201. Ingaramo, Paola Alarcón, Ramiro Muñoz-de-Toro, Mónica and Luque, Enrique H. 2020. Are glyphosate and glyphosate-based herbicides endocrine disruptors that alter female fertility?. Molecular and Cellular Endocrinology, Vol. 518, Issue. , p. 110934. Wang, Hongwei Song, Shikui Peng, Fei Yang, Fei Chen, Tian Li, Xin Cheng, Xiyao He, Yijun Huang, Yongqi and Su, Zhengding 2020. Whole-genome and enzymatic analyses of an androstenedione-producing Mycobacterium strain with residual phytosterol-degrading pathways. Microbial Cell Factories, Vol. 19, Issue. 1, Rumph, Jelonia T. Stephens, Victoria R. Archibong, Anthony E. Osteen, Kevin G. and Bruner-Tran, Kaylon L. 2020. Animal Models for Endometriosis. Vol. 232, Issue. , p. 57. Honour, John William 2023. Steroids in the Laboratory and Clinical Practice. p. 753.