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

Published online by Cambridge University Press:  08 March 2018

Chithra Janardhanan Susheelamma ,
Sathy M. Pillai  and
Sivakumari Asha Nair
Chithra Janardhanan Susheelamma
Affiliation:
Cancer Research Program-4, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
Sathy M. Pillai
Affiliation:
Samad IVF Hospital, Thiruvananthapuram 695035, Kerala, India
Sivakumari Asha Nair*
Affiliation:
Cancer Research Program-4, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
*
Author for Correspondence: Sivakumari Asha Nair, Cancer research program-4, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India. Tel: 0471-2529501; E-mail: [email protected]
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Abstract

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.

Keywords

Endometrial stem cellsoestrogenprogesteroneWntNotchHedgehog
Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 20 , 2018 , e2
Copyright
Copyright © Cambridge University Press 2018 

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References

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