Skip to main content

Advertisement

SpringerLink
Log in

Uterine Stem Cells and Benign Gynecological Disorders: Role in Pathobiology and Therapeutic Implications

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Stem cells in the endometrium and myometrium possess an immense regenerative potential which is necessary to maintain the menstrual cycle and support pregnancy. These cells, as well as bone marrow stem cells, have also been implicated in the development of common benign gynecological disorders including leiomyomas, endometriosis and adenomyosis. Current evidence suggests the conversion of uterine stem cells to tumor initiating stem cells in leiomyomas, endometriosis stem cells, and adenomyosis stem cells, acquiring genetic and epigenetic alterations for the progression of each benign condition. In this comprehensive review, we aim to summarize the progress that has been made to characterize the involvement of stem cells in the pathogenesis of benign gynecologic conditions which, despite their enormous burden, are not yet fully understood. We focus on the stem cell characteristics and aberrations that contribute to the development of benign gynecological disorders and the possible clinical implications of what is known so far. Lastly, we discuss the role of uterine stem cells in the setting of regenerative medicine, particularly in the treatment of Asherman syndrome.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Abdel-Rasheed, M., Nour Eldeen, G., Mahmoud, M., ElHefnawi, M., Abu-Shahba, N., Reda, M., et al. (2017). MicroRNA expression analysis in endometriotic serum treated mesenchymal stem cells. EXCLI Journal, 16, 852–867. https://doi.org/10.17179/excli2017-101.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Afrin, S., Islam, M. S., Patzkowsky, K., Malik, M., Catherino, W. H., Segars, J. H., et al. (2020). Simvastatin ameliorates altered mechanotransduction in uterine leiomyoma cells. American Journal of Obstetrics and Gynecology. https://doi.org/10.1016/j.ajog.2020.05.012.

  3. Ahn, S. H., Singh, V., & Tayade, C. (2017). Biomarkers in endometriosis: Challenges and opportunities. Fertility and Sterility, 107(3), 523–532. https://doi.org/10.1016/j.fertnstert.2017.01.009.

    Article  CAS  PubMed  Google Scholar 

  4. AlAshqar, A., Patzkowsky, K., Afrin, S., Wild, R., Taylor, H. S., & Borahay, M. A. (2019). Cardiometabolic risk factors and benign gynecologic disorders. Obstetrical & Gynecological Survey, 74(11), 661–673. https://doi.org/10.1097/OGX.0000000000000718.

    Article  Google Scholar 

  5. Alawadhi, F., Du, H., Cakmak, H., & Taylor, H. S. (2014). Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman’s syndrome. PLoS One, 9(5), e96662. https://doi.org/10.1371/journal.pone.0096662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Alcayaga-Miranda, F., Cuenca, J., Luz-Crawford, P., Aguila-Diaz, C., Fernandez, A., Figueroa, F. E., et al. (2015). Characterization of menstrual stem cells: Angiogenic effect, migration and hematopoietic stem cell support in comparison with bone marrow mesenchymal stem cells. Stem Cell Research & Therapy, 6, 32. https://doi.org/10.1186/s13287-015-0013-5.

    Article  CAS  Google Scholar 

  7. Arango, N. A., Szotek, P. P., Manganaro, T. F., Oliva, E., Donahoe, P. K., & Teixeira, J. (2005). Conditional deletion of beta-catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium. Developmental Biology, 288(1), 276–283. https://doi.org/10.1016/j.ydbio.2005.09.045.

    Article  CAS  PubMed  Google Scholar 

  8. Arici, A., & Sozen, I. (2000). Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertility and Sterility, 73(5), 1006–1011.

    Article  CAS  Google Scholar 

  9. Azedi, F., Kazemnejad, S., Zarnani, A. H., Behzadi, G., Vasei, M., Khanmohammadi, M., et al. (2014). Differentiation potential of menstrual blood- versus bone marrow-stem cells into glial-like cells. Cell Biology International, 38(5), 615–624. https://doi.org/10.1002/cbin.10245.

    Article  CAS  PubMed  Google Scholar 

  10. Azizi, R., Aghebati-Maleki, L., Nouri, M., Marofi, F., Negargar, S., & Yousefi, M. (2018). Stem cell therapy in Asherman syndrome and thin endometrium: Stem cell- based therapy. Biomedicine & Pharmacotherapy, 102, 333–343. https://doi.org/10.1016/j.biopha.2018.03.091.

    Article  CAS  Google Scholar 

  11. Azziz, R. (1989). Adenomyosis: Current perspectives. Obstetrics and Gynecology Clinics of North America, 16(1), 221–235.

    CAS  PubMed  Google Scholar 

  12. Barragan, F., Irwin, J. C., Balayan, S., Erikson, D. W., Chen, J. C., Houshdaran, S., 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(5), 118. https://doi.org/10.1095/biolreprod.115.136010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bazot, M., Cortez, A., Darai, E., Rouger, J., Chopier, J., Antoine, J. M., et al. (2001). Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: Correlation with histopathology. Human Reproduction, 16(11), 2427–2433. https://doi.org/10.1093/humrep/16.11.2427.

    Article  CAS  PubMed  Google Scholar 

  14. Bhartiya, D., & James, K. (2017). Very small embryonic-like stem cells (VSELs) in adult mouse uterine perimetrium and myometrium. Journal of Ovarian Research, 10(1), 29. https://doi.org/10.1186/s13048-017-0324-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bhartiya, D., Shaikh, A., Anand, S., Patel, H., Kapoor, S., Sriraman, K., et al. (2016). Endogenous, very small embryonic-like stem cells: Critical review, therapeutic potential and a look ahead. Human Reproduction Update, 23(1), 41–76. https://doi.org/10.1093/humupd/dmw030.

    Article  CAS  PubMed  Google Scholar 

  16. Borahay, M. A., Kilic, G. S., Yallampalli, C., Snyder, R. R., Hankins, G. D., Al-Hendy, A., et al. (2014). Simvastatin potently induces calcium-dependent apoptosis of human leiomyoma cells. The Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M114.583575.

  17. Borahay, M. A., Al-Hendy, A., Kilic, G. S., & Boehning, D. (2015). Signaling pathways in leiomyoma: Understanding pathobiology and implications for therapy. Molecular Medicine, 21, 242–256. https://doi.org/10.2119/molmed.2014.00053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Borahay, M. A., Vincent, K., Motamedi, M., Sbrana, E., Kilic, G. S., Al-Hendy, A., et al. (2015). Novel effects of simvastatin on uterine fibroids: In vitro and patient-derived xenograft mouse model study. American Journal of Obstetrics and Gynecology. https://doi.org/10.1016/j.ajog.2015.03.055.

  19. Borahay, M. A., Asoglu, M. R., Mas, A., Adam, S., Kilic, G. S., & Al-Hendy, A. (2016). Estrogen receptors and signaling in fibroids: Role in pathobiology and therapeutic implications. Reproductive Sciences. https://doi.org/10.1177/1933719116678686.

  20. Borahay, M. A., Fang, X., Baillargeon, J. G., Kilic, G. S., Boehning, D. F., & Kuo, Y. F. (2016). Statin use and uterine fibroid risk in hyperlipidemia patients: A nested case-control study. American Journal of Obstetrics and Gynecology. https://doi.org/10.1016/j.ajog.2016.06.036.

  21. Brakta, S., Mas, A., & Al-Hendy, A. (2018). The ontogeny of myometrial stem cells in OCT4-GFP transgenic mouse model. Stem Cell Research & Therapy, 9(1), 333. https://doi.org/10.1186/s13287-018-1079-7.

    Article  CAS  Google Scholar 

  22. Bulun, S. E. (2009). Endometriosis. The New England Journal of Medicine, 360(3), 268–279. https://doi.org/10.1056/NEJMra0804690.

    Article  CAS  PubMed  Google Scholar 

  23. Bulun, S. E. (2013). Uterine fibroids. The New England Journal of Medicine, 369(14), 1344–1355. https://doi.org/10.1056/NEJMra1209993.

    Article  CAS  PubMed  Google Scholar 

  24. Burney, R. O., & Giudice, L. C. (2012). Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility, 98(3), 511–519. https://doi.org/10.1016/j.fertnstert.2012.06.029.

    Article  CAS  PubMed  Google Scholar 

  25. Cao, Y., Sun, H., Zhu, H., Zhu, X., Tang, X., Yan, G., et al. (2018). Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: A phase I clinical trial. Stem Cell Research & Therapy, 9(1), 192. https://doi.org/10.1186/s13287-018-0904-3.

    Article  Google Scholar 

  26. Cervello, I., Gil-Sanchis, C., Mas, A., Delgado-Rosas, F., Martinez-Conejero, J. A., Galan, A., et al. (2010). Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PLoS One, 5(6), e10964. https://doi.org/10.1371/journal.pone.0010964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chagastelles, P. C., & Nardi, N. B. (2011). Biology of stem cells: An overview. Kidney International Supplement, 1(3), 63–67. https://doi.org/10.1038/kisup.2011.15.

    Article  Google Scholar 

  28. Challen, G. A., & Little, M. H. (2006). A side order of stem cells: The SP phenotype. Stem Cells, 24(1), 3–12. https://doi.org/10.1634/stemcells.2005-0116.

    Article  PubMed  Google Scholar 

  29. Chan, R. W., Schwab, K. E., & Gargett, C. E. (2004). Clonogenicity of human endometrial epithelial and stromal cells. Biology of Reproduction, 70(6), 1738–1750. https://doi.org/10.1095/biolreprod.103.024109.

    Article  CAS  PubMed  Google Scholar 

  30. Chang, H. L., Senaratne, T. N., Zhang, L., Szotek, P. P., Stewart, E., Dombkowski, D., et al. (2010). Uterine leiomyomas exhibit fewer stem/progenitor cell characteristics when compared with corresponding normal myometrium. Reproductive Sciences, 17(2), 158–167. https://doi.org/10.1177/1933719109348924.

    Article  PubMed  Google Scholar 

  31. Chen, Y. J., Li, H. Y., Chang, Y. L., Yuan, C. C., Tai, L. K., Lu, K. H., et al. (2010). Suppression of migratory/invasive ability and induction of apoptosis in adenomyosis-derived mesenchymal stem cells by cyclooxygenase-2 inhibitors. Fertility and Sterility, 94(6), 1972–1979, 9 e1–4. https://doi.org/10.1016/j.fertnstert.2010.01.070.

    Article  CAS  PubMed  Google Scholar 

  32. Chen, Y. Z., Wang, J. H., Yan, J., Liang, Y., Zhang, X. F., & Zhou, F. (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. https://doi.org/10.1016/j.ejogrb.2013.11.025.

    Article  CAS  PubMed  Google Scholar 

  33. Chen, H. Y., Huang, T. C., Lin, L. C., Shieh, T. M., Wu, C. H., Wang, K. L., et al. (2018). Fucoidan inhibits the proliferation of leiomyoma cells and decreases extracellular matrix-associated protein expression. Cellular Physiology and Biochemistry, 49(5), 1970–1986. https://doi.org/10.1159/000493660.

    Article  CAS  PubMed  Google Scholar 

  34. Chen, P., Mamillapalli, R., Habata, S., & Taylor, H. S. (2020). Endometriosis cell proliferation induced by bone marrow mesenchymal stem cells. Reproductive Sciences. https://doi.org/10.1007/s43032-020-00294-4.

  35. Cheng, Y., Li, L., Wang, D., Guo, Q., He, Y., Liang, T., et al. (2017). Characteristics of human endometrium-derived mesenchymal stem cells and their tropism to endometriosis. Stem Cells International, 2017, 4794827. https://doi.org/10.1155/2017/4794827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Conforti, A., Alviggi, C., Mollo, A., De Placido, G., & Magos, A. (2013). The management of Asherman syndrome: A review of literature. Reproductive Biology and Endocrinology, 11, 118. https://doi.org/10.1186/1477-7827-11-118.

    Article  PubMed  Google Scholar 

  37. Diao, R., Wei, W., Zhao, J., Tian, F., Cai, X., & Duan, Y. G. (2017). CCL19/CCR7 contributes to the pathogenesis of endometriosis via PI3K/Akt pathway by regulating the proliferation and invasion of ESCs. The American Journal of Reproductive Immunology, 78(5). https://doi.org/10.1111/aji.12744.

  38. Dracxler, R. C., Oh, C., Kalmbach, K., Wang, F., Liu, L., Kallas, E. G., et al. (2014). Peripheral blood telomere content is greater in patients with endometriosis than in controls. Reproductive Sciences, 21(12), 1465–1471. https://doi.org/10.1177/1933719114527353.

    Article  CAS  PubMed  Google Scholar 

  39. Dreisler, E., & Kjer, J. J. (2019). Asherman’s syndrome: Current perspectives on diagnosis and management. International Journal of Women’s Health, 11, 191–198. https://doi.org/10.2147/IJWH.S165474.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Du, H., & Taylor, H. S. (2007). Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells, 25(8), 2082–2086. https://doi.org/10.1634/stemcells.2006-0828.

    Article  CAS  PubMed  Google Scholar 

  41. Du, H., Naqvi, H., & Taylor, H. S. (2012). Ischemia/reperfusion injury promotes and granulocyte-colony stimulating factor inhibits migration of bone marrow-derived stem cells to endometrium. Stem Cells and Development, 21(18), 3324–3331. https://doi.org/10.1089/scd.2011.0193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ebrahim, N., Mostafa, O., El Dosoky, R. E., Ahmed, I. A., Saad, A. S., Mostafa, A., et al. (2018). Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model. Stem Cell Research & Therapy, 9(1), 175. https://doi.org/10.1186/s13287-018-0924-z.

    Article  CAS  Google Scholar 

  43. Elkafas, H., Qiwei, Y., & Al-Hendy, A. (2017). Origin of uterine fibroids: Conversion of myometrial stem cells to tumor-initiating cells. Seminars in Reproductive Medicine, 35(6), 481–486. https://doi.org/10.1055/s-0037-1607205.

    Article  PubMed  Google Scholar 

  44. Elkafas, H., Ali, M., Elmorsy, E., Kamel, R., Thompson, W. E., Badary, O., et al. (2020). Vitamin D3 ameliorates DNA damage caused by developmental exposure to endocrine disruptors in the uterine myometrial stem cells of Eker rats. Cells, 9(6). https://doi.org/10.3390/cells9061459.

  45. Eskenazi, B., & Warner, M. L. (1997). Epidemiology of endometriosis. Obstetrics and Gynecology Clinics of North America, 24(2), 235–258. https://doi.org/10.1016/s0889-8545(05)70302-8.

    Article  CAS  PubMed  Google Scholar 

  46. Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819), 154–156. https://doi.org/10.1038/292154a0.

    Article  CAS  PubMed  Google Scholar 

  47. Fayazi, M., Salehnia, M., & Ziaei, S. (2015). Differentiation of human CD146-positive endometrial stem cells to adipogenic-, osteogenic-, neural progenitor-, and glial-like cells. In Vitro Cellular & Developmental Biology Animal, 51(4), 408–414. https://doi.org/10.1007/s11626-014-9842-2.

    Article  CAS  Google Scholar 

  48. Ferenczy, A. (1998). Pathophysiology of adenomyosis. Human Reproduction Update, 4(4), 312–322. https://doi.org/10.1093/humupd/4.4.312.

    Article  CAS  PubMed  Google Scholar 

  49. Figueira, P. G., Abrao, M. S., Krikun, G., & Taylor, H. S. (2011). Stem cells in endometrium and their role in the pathogenesis of endometriosis. Annals of the New York Academy of Sciences, 1221, 10–17. https://doi.org/10.1111/j.1749-6632.2011.05969.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Forte, A., Schettino, M. T., Finicelli, M., Cipollaro, M., Colacurci, N., Cobellis, L., et al. (2009). Expression pattern of stemness-related genes in human endometrial and endometriotic tissues. Molecular Medicine, 15(11–12), 392–401. https://doi.org/10.2119/molmed.2009.00068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fritton, K., & Borahay, M. A. (2017). New and emerging therapies for uterine fibroids. Seminars in Reproductive Medicine, 35(6), 549–559. https://doi.org/10.1055/s-0037-1606303.

    Article  CAS  PubMed  Google Scholar 

  52. Fuchs, E., Tumbar, T., & Guasch, G. (2004). Socializing with the neighbors: Stem cells and their niche. Cell, 116(6), 769–778. https://doi.org/10.1016/s0092-8674(04)00255-7.

    Article  CAS  PubMed  Google Scholar 

  53. Garcia-Solares, J., Donnez, J., Donnez, O., & Dolmans, M. M. (2018). Pathogenesis of uterine adenomyosis: Invagination or metaplasia? Fertility and Sterility, 109(3), 371–379. https://doi.org/10.1016/j.fertnstert.2017.12.030.

    Article  PubMed  Google Scholar 

  54. Gargett, C. E. (2007). Uterine stem cells: What is the evidence? Human Reproduction Update, 13(1), 87–101. https://doi.org/10.1093/humupd/dml045.

    Article  CAS  PubMed  Google Scholar 

  55. Gargett, C. E., Schwab, K. E., Zillwood, R. M., Nguyen, H. P., & Wu, D. (2009). Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biology of Reproduction, 80(6), 1136–1145. https://doi.org/10.1095/biolreprod.108.075226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gargett, C. E., Schwab, K. E., & Deane, J. A. (2016). Endometrial stem/progenitor cells: The first 10 years. Human Reproduction Update, 22(2), 137–163. https://doi.org/10.1093/humupd/dmv051.

    Article  CAS  PubMed  Google Scholar 

  57. Gil-Sanchis, C., Cervello, I., Mas, A., Faus, A., Pellicer, A., & Simon, C. (2013). Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) as a putative human endometrial stem cell marker. Molecular Human Reproduction, 19(7), 407–414. https://doi.org/10.1093/molehr/gat014.

    Article  CAS  PubMed  Google Scholar 

  58. Golebiewska, A., Brons, N. H., Bjerkvig, R., & Niclou, S. P. (2011). Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell, 8(2), 136–147. https://doi.org/10.1016/j.stem.2011.01.007.

    Article  CAS  PubMed  Google Scholar 

  59. Gotte, M., Wolf, M., Staebler, A., Buchweitz, O., Kiesel, L., & Schuring, A. N. (2011). Aberrant expression of the pluripotency marker SOX-2 in endometriosis. Fertility and Sterility, 95(1), 338–341. https://doi.org/10.1016/j.fertnstert.2010.08.006.

    Article  CAS  PubMed  Google Scholar 

  60. Gupta, D., Hull, M. L., Fraser, I., Miller, L., Bossuyt, P. M., Johnson, N., et al. (2016). Endometrial biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database of Systematic Reviews, 4, CD012165. https://doi.org/10.1002/14651858.CD012165.

    Article  Google Scholar 

  61. Hapangama, D. K., Turner, M. A., Drury, J. A., Quenby, S., Saretzki, G., Martin-Ruiz, C., et al. (2008). Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length. Human Reproduction, 23(7), 1511–1519. https://doi.org/10.1093/humrep/den172.

    Article  CAS  PubMed  Google Scholar 

  62. Hapangama, D. K., Drury, J., Da Silva, L., Al-Lamee, H., Earp, A., Valentijn, A. J., et al. (2019). Abnormally located SSEA1+/SOX9+ endometrial epithelial cells with a basalis-like phenotype in the eutopic functionalis layer may play a role in the pathogenesis of endometriosis. Human Reproduction, 34(1), 56–68. https://doi.org/10.1093/humrep/dey336.

    Article  CAS  PubMed  Google Scholar 

  63. Harada, H., Tsuda, Y., Yabuki, K., Shiba, E., Uchihashi, K., Matsuyama, A., et al. (2018). Inhibition of WNT/beta-catenin signaling under serum starvation and hypoxia induces adipocytic transdifferentiation in human leiomyoma cells. Laboratory Investigation, 98(4), 439–448. https://doi.org/10.1038/s41374-017-0020-5.

    Article  CAS  PubMed  Google Scholar 

  64. Hida, N., Nishiyama, N., Miyoshi, S., Kira, S., Segawa, K., Uyama, T., et al. (2008). Novel cardiac precursor-like cells from human menstrual blood-derived mesenchymal cells. Stem Cells, 26(7), 1695–1704. https://doi.org/10.1634/stemcells.2007-0826.

    Article  CAS  PubMed  Google Scholar 

  65. Hodge, J. C., Park, P. J., Dreyfuss, J. M., Assil-Kishawi, I., Somasundaram, P., Semere, L. G., et al. (2009). Identifying the molecular signature of the interstitial deletion 7q subgroup of uterine leiomyomata using a paired analysis. Genes, Chromosomes & Cancer, 48(10), 865–885. https://doi.org/10.1002/gcc.20692.

    Article  CAS  Google Scholar 

  66. Hooker, A. B., Lemmers, M., Thurkow, A. L., Heymans, M. W., Opmeer, B. C., Brolmann, H. A., et al. (2014). Systematic review and meta-analysis of intrauterine adhesions after miscarriage: Prevalence, risk factors and long-term reproductive outcome. Human Reproduction Update, 20(2), 262–278. https://doi.org/10.1093/humupd/dmt045.

    Article  CAS  PubMed  Google Scholar 

  67. Hsu, C. Y., Hsieh, T. H., Tsai, C. F., Tsai, H. P., Chen, H. S., Chang, Y., et al. (2014). miRNA-199a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. The Journal of Pathology, 232(3), 330–343. https://doi.org/10.1002/path.4295.

    Article  CAS  PubMed  Google Scholar 

  68. Ibrahim, M. G., Chiantera, V., Frangini, S., Younes, S., Kohler, C., Taube, E. T., et al. (2015). Ultramicro-trauma in the endometrial-myometrial junctional zone and pale cell migration in adenomyosis. Fertility and Sterility, 104(6), 1475–1483 e1–3. https://doi.org/10.1016/j.fertnstert.2015.09.002.

    Article  CAS  PubMed  Google Scholar 

  69. Ikhena, D. E., Liu, S., Kujawa, S., Esencan, E., Coon, J. S., Robins, J., et al. (2018). RANKL/RANK pathway and its inhibitor RANK-Fc in uterine leiomyoma growth. The Journal of Clinical Endocrinology and Metabolism, 103(5), 1842–1849. https://doi.org/10.1210/jc.2017-01585.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ikoma, T., Kyo, S., Maida, Y., Ozaki, S., Takakura, M., Nakao, S., et al. (2009). Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. The American Journal of Obstetrics and Gynecology, 201(6), 608 e1–608 e8. https://doi.org/10.1016/j.ajog.2009.07.026.

    Article  CAS  Google Scholar 

  71. Inagaki, N., Ung, L., Otani, T., Wilkinson, D., & Lopata, A. (2003). Uterine cavity matrix metalloproteinases and cytokines in patients with leiomyoma, adenomyosis or endometrial polyp. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 111(2), 197–203. https://doi.org/10.1016/s0301-2115(03)00244-6.

    Article  CAS  PubMed  Google Scholar 

  72. Izadpanah, R., Schachtele, D. J., Pfnur, A. B., Lin, D., Slakey, D. P., Kadowitz, P. J., et al. (2015). The impact of statins on biological characteristics of stem cells provides a novel explanation for their pleiotropic beneficial and adverse clinical effects. American Journal of Physiology Cell Physiology, 309(8), C522–C531. https://doi.org/10.1152/ajpcell.00406.2014.

    Article  CAS  PubMed  Google Scholar 

  73. Jabbour, H. N., Kelly, R. W., Fraser, H. M., & Critchley, H. O. (2006). Endocrine regulation of menstruation. Endocrine Reviews, 27(1), 17–46. https://doi.org/10.1210/er.2004-0021.

    Article  CAS  PubMed  Google Scholar 

  74. James, K., Bhartiya, D., Ganguly, R., Kaushik, A., Gala, K., Singh, P., et al. (2018). Gonadotropin and steroid hormones regulate pluripotent very small embryonic-like stem cells in adult mouse uterine endometrium. Journal of Ovarian Research, 11(1), 83. https://doi.org/10.1186/s13048-018-0454-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kao, A. P., Wang, K. H., Chang, C. C., Lee, J. N., Long, C. Y., Chen, H. S., 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(4), 1308–1315 e1. https://doi.org/10.1016/j.fertnstert.2010.09.064.

    Article  CAS  PubMed  Google Scholar 

  76. Kato, K., Yoshimoto, M., Kato, K., Adachi, S., Yamayoshi, A., Arima, T., et al. (2007). Characterization of side-population cells in human normal endometrium. Human Reproduction, 22(5), 1214–1223. https://doi.org/10.1093/humrep/del514.

    Article  CAS  PubMed  Google Scholar 

  77. Kawai, H., Tsujigiwa, H., Siar, C. H., Nakano, K., Takabatake, K., Fujii, M., et al. (2018). Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis. International Journal of Medical Sciences, 15(12), 1406–1414. https://doi.org/10.7150/ijms.24370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Khoury, M., Alcayaga-Miranda, F., Illanes, S. E., & Figueroa, F. E. (2014). The promising potential of menstrual stem cells for antenatal diagnosis and cell therapy. Frontiers in Immunology, 5, 205. https://doi.org/10.3389/fimmu.2014.00205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kilic, S., Yuksel, B., Pinarli, F., Albayrak, A., Boztok, B., & Delibasi, T. (2014). Effect of stem cell application on Asherman syndrome, an experimental rat model. Journal of Assisted Reproduction and Genetics, 31(8), 975–982. https://doi.org/10.1007/s10815-014-0268-2.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kishi, Y., Suginami, H., Kuramori, R., Yabuta, M., Suginami, R., & Taniguchi, F. (2012). Four subtypes of adenomyosis assessed by magnetic resonance imaging and their specification. The American Journal of Obstetrics and Gynecology, 207(2), 114 e1–114 e7. https://doi.org/10.1016/j.ajog.2012.06.027.

    Article  Google Scholar 

  81. Krause, D. S., Theise, N. D., Collector, M. I., Henegariu, O., Hwang, S., Gardner, R., et al. (2001). Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 105(3), 369–377. https://doi.org/10.1016/s0092-8674(01)00328-2.

    Article  CAS  PubMed  Google Scholar 

  82. Laschke, M. W., & Menger, M. D. (2018). Basic mechanisms of vascularization in endometriosis and their clinical implications. Human Reproduction Update, 24(2), 207–224. https://doi.org/10.1093/humupd/dmy001.

    Article  CAS  PubMed  Google Scholar 

  83. Leconte, M., Chouzenoux, S., Nicco, C., Chereau, C., Arkwright, S., Santulli, P., et al. (2014). Role of the CXCL12-CXCR4 axis in the development of deep rectal endometriosis. Journal of Reproductive Immunology, 103, 45–52. https://doi.org/10.1016/j.jri.2013.12.121.

    Article  CAS  PubMed  Google Scholar 

  84. Leyendecker, G., Herbertz, M., Kunz, G., & Mall, G. (2002). Endometriosis results from the dislocation of basal endometrium. Human Reproduction, 17(10), 2725–2736. https://doi.org/10.1093/humrep/17.10.2725.

    Article  CAS  PubMed  Google Scholar 

  85. Li, H. Y., Chen, Y. J., Chen, S. J., Kao, C. L., Tseng, L. M., Lo, W. L., et al. (2010). Induction of insulin-producing cells derived from endometrial mesenchymal stem-like cells. The Journal of Pharmacology and Experimental Therapeutics, 335(3), 817–829. https://doi.org/10.1124/jpet.110.169284.

    Article  CAS  PubMed  Google Scholar 

  86. Liu, X. J., Bai, X. G., Teng, Y. L., Song, L., Lu, N., & Yang, R. Q. (2016). miRNA-15a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. European Review for Medical and Pharmacological Sciences, 20(16), 3319–3326.

    PubMed  Google Scholar 

  87. Liu, Y., Niu, R., Yang, F., Yan, Y., Liang, S., Sun, Y., et al. (2018). Biological characteristics of human menstrual blood-derived endometrial stem cells. Journal of Cellular and Molecular Medicine, 22(3), 1627–1639. https://doi.org/10.1111/jcmm.13437.

    Article  CAS  PubMed  Google Scholar 

  88. Liu, S., Yin, P., Kujawa, S. A., Coon, J. S., Okeigwe, I., & Bulun, S. E. (2019). Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma. Oncogene, 38(15), 2722–2735. https://doi.org/10.1038/s41388-018-0612-6.

    Article  CAS  PubMed  Google Scholar 

  89. Liu, S., Yin, P., Xu, J., Dotts, A. J., Kujawa, S. A., Coon, V. J., et al. (2020). Targeting DNA methylation depletes uterine leiomyoma stem-cell enriched population by stimulating their differentiation. Endocrinology. https://doi.org/10.1210/endocr/bqaa143.

  90. Liu, S., Yin, P., Dotts, A. J., Kujawa, S. A., Coon, V. J., Wei, J. J., et al. (2020). Activation of protein kinase B by WNT4 as a regulator of uterine leiomyoma stem cell function. Fertility and Sterility. https://doi.org/10.1016/j.fertnstert.2020.06.045.

  91. Lupicka, M., Socha, B., Szczepanska, A., & Korzekwa, A. (2015). Expression of pluripotency markers in the bovine uterus with adenomyosis. Reproductive Biology and Endocrinology, 13, 110. https://doi.org/10.1186/s12958-015-0106-0.

    Article  CAS  PubMed  Google Scholar 

  92. Ma, Y., Huang, Y. X., & Chen, Y. Y. (2017). miRNA34a5p downregulation of VEGFA in endometrial stem cells contributes to the pathogenesis of endometriosis. Molecular Medicine Reports, 16(6), 8259–8264. https://doi.org/10.3892/mmr.2017.7677.

    Article  CAS  PubMed  Google Scholar 

  93. MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Developmental Cell, 17(1), 9–26. https://doi.org/10.1016/j.devcel.2009.06.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Makinen, N., Vahteristo, P., Kampjarvi, K., Arola, J., Butzow, R., & Aaltonen, L. A. (2013). MED12 exon 2 mutations in histopathological uterine leiomyoma variants. European Journal of Human Genetics, 21(11), 1300–1303. https://doi.org/10.1038/ejhg.2013.33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Malik, M., Britten, J., Borahay, M., Segars, J., & Catherino, W. H. (2018). Simvastatin, at clinically relevant concentrations, affects human uterine leiomyoma growth and extracellular matrix production. Fertility and Sterility, 110(7), 1398–1407 e1. https://doi.org/10.1016/j.fertnstert.2018.07.024.

    Article  CAS  PubMed  Google Scholar 

  96. Markowski, D. N., Bartnitzke, S., Loning, T., Drieschner, N., Helmke, B. M., & Bullerdiek, J. (2012). MED12 mutations in uterine fibroids – their relationship to cytogenetic subgroups. International Journal of Cancer, 131(7), 1528–1536. https://doi.org/10.1002/ijc.27424.

    Article  CAS  PubMed  Google Scholar 

  97. Martin, J. D., Jr., & Hauck, A. E. (1985). Endometriosis in the male. The American Surgeon, 51(7), 426–430.

    PubMed  Google Scholar 

  98. Mas, A., Cervello, I., Gil-Sanchis, C., Faus, A., Ferro, J., Pellicer, A., et al. (2012). Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells. Fertility and Sterility, 98(3), 741–751 e6. https://doi.org/10.1016/j.fertnstert.2012.04.044.

    Article  PubMed  Google Scholar 

  99. Mas, A., Nair, S., Laknaur, A., Simon, C., Diamond, M. P., & Al-Hendy, A. (2015). Stro-1/CD44 as putative human myometrial and fibroid stem cell markers. Fertility and Sterility, 104(1), 225–234 e3. https://doi.org/10.1016/j.fertnstert.2015.04.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mas, A., Cervello, I., Fernandez-Alvarez, A., Faus, A., Diaz, A., Burgues, O., et al. (2015). Overexpression of the truncated form of high mobility group A proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation. Molecular Human Reproduction, 21(4), 330–338. https://doi.org/10.1093/molehr/gau114.

    Article  CAS  PubMed  Google Scholar 

  101. Mas, A., Stone, L., O’Connor, P. M., Yang, Q., Kleven, D., Simon, C., et al. (2017). Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. Stem Cells, 35(3), 666–678. https://doi.org/10.1002/stem.2519.

    Article  CAS  PubMed  Google Scholar 

  102. Mashayekhi, P., Noruzinia, M., Zeinali, S., & Khodaverdi, S. (2019). Endometriotic mesenchymal stem cells epigenetic pathogenesis: Deregulation of miR-200b, miR-145, and let7b in a functional imbalanced epigenetic disease. Cell Journal, 21(2), 179–185. https://doi.org/10.22074/cellj.2019.5903.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Masuda, H., Matsuzaki, Y., Hiratsu, E., Ono, M., Nagashima, T., Kajitani, T., et al. (2010). Stem cell-like properties of the endometrial side population: Implication in endometrial regeneration. PLoS One, 5(4), e10387. https://doi.org/10.1371/journal.pone.0010387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Masuda, H., Anwar, S. S., Buhring, H. J., Rao, J. R., & Gargett, C. E. (2012). A novel marker of human endometrial mesenchymal stem-like cells. Cell Transplantation, 21(10), 2201–2214. https://doi.org/10.3727/096368911X637362.

    Article  PubMed  Google Scholar 

  105. May, K. E., Villar, J., Kirtley, S., Kennedy, S. H., & Becker, C. M. (2011). Endometrial alterations in endometriosis: A systematic review of putative biomarkers. Human Reproduction Update, 17(5), 637–653. https://doi.org/10.1093/humupd/dmr013.

    Article  CAS  PubMed  Google Scholar 

  106. McElin, T. W., & Bird, C. C. (1974). Adenomyosis of the uterus. Obstetrics and Gynecology Annual, 3(0), 425–441.

    CAS  PubMed  Google Scholar 

  107. McGuire, M. M., Yatsenko, A., Hoffner, L., Jones, M., Surti, U., & Rajkovic, A. (2012). Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PLoS One, 7(3), e33251. https://doi.org/10.1371/journal.pone.0033251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mehine, M., Makinen, N., Heinonen, H. R., Aaltonen, L. A., & Vahteristo, P. (2014). Genomics of uterine leiomyomas: Insights from high-throughput sequencing. Fertility and Sterility, 102(3), 621–629. https://doi.org/10.1016/j.fertnstert.2014.06.050.

    Article  CAS  PubMed  Google Scholar 

  109. Meng, X., Ichim, T. E., Zhong, J., Rogers, A., Yin, Z., Jackson, J., et al. (2007). Endometrial regenerative cells: A novel stem cell population. Journal of Translational Medicine, 5, 57. https://doi.org/10.1186/1479-5876-5-57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mints, M., Jansson, M., Sadeghi, B., Westgren, M., Uzunel, M., Hassan, M., et al. (2008). Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient. Human Reproduction, 23(1), 139–143. https://doi.org/10.1093/humrep/dem342.

    Article  CAS  PubMed  Google Scholar 

  111. Miyazaki, K., Maruyama, T., Masuda, H., Yamasaki, A., Uchida, S., Oda, H., et al. (2012). Stem cell-like differentiation potentials of endometrial side population cells as revealed by a newly developed in vivo endometrial stem cell assay. PLoS One, 7(12), e50749. https://doi.org/10.1371/journal.pone.0050749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mohyeldin, A., Garzon-Muvdi, T., & Quinones-Hinojosa, A. (2010). Oxygen in stem cell biology: A critical component of the stem cell niche. Cell Stem Cell, 7(2), 150–161. https://doi.org/10.1016/j.stem.2010.07.007.

    Article  CAS  PubMed  Google Scholar 

  113. Moravek, M. B., Yin, P., Ono, M., Coon, J. S., Dyson, M. T., Navarro, A., et al. (2015). Ovarian steroids, stem cells and uterine leiomyoma: Therapeutic implications. Human Reproduction Update, 21(1), 1–12. https://doi.org/10.1093/humupd/dmu048.

    Article  CAS  PubMed  Google Scholar 

  114. Moravek, M. B., Yin, P., Coon, J. S., Ono, M., Druschitz, S. A., Malpani, S. S., et al. (2017). Paracrine pathways in uterine leiomyoma stem cells involve insulin like growth factor 2 and insulin receptor A. The Journal of Clinical Endocrinology and Metabolism, 102(5), 1588–1595. https://doi.org/10.1210/jc.2016-3497.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Moridi, I., Mamillapalli, R., Cosar, E., Ersoy, G. S., & Taylor, H. S. (2017). Bone marrow stem cell chemotactic activity is induced by elevated CXCl12 in endometriosis. Reproductive Sciences, 24(4), 526–533. https://doi.org/10.1177/1933719116672587.

    Article  CAS  PubMed  Google Scholar 

  116. Moridi, I., Mamillapalli, R., Kodaman, P. H., Habata, S., Dang, T., & Taylor, H. S. (2020). CXCL12 attracts bone marrow-derived cells to uterine leiomyomas. Reproductive Sciences, 27(9), 1724–1730. https://doi.org/10.1007/s43032-020-00166-x.

    Article  CAS  PubMed  Google Scholar 

  117. Mou, X. Z., Lin, J., Chen, J. Y., Li, Y. F., Wu, X. X., Xiang, B. Y., et al. (2013). Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells. Journal of Zhejiang University Science B, 14(11), 961–972. https://doi.org/10.1631/jzus.B1300081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Musina, R. A., Belyavski, A. V., Tarusova, O. V., Solovyova, E. V., & Sukhikh, G. T. (2008). Endometrial mesenchymal stem cells isolated from the menstrual blood. Bulletin of Experimental Biology and Medicine, 145(4), 539–543. https://doi.org/10.1007/s10517-008-0136-0.

    Article  CAS  PubMed  Google Scholar 

  119. Nagori, C. B., Panchal, S. Y., & Patel, H. (2011). Endometrial regeneration using autologous adult stem cells followed by conception by in vitro fertilization in a patient of severe Asherman’s syndrome. The Journal of Human Reproductive Sciences, 4(1), 43–48. https://doi.org/10.4103/0974-1208.82360.

    Article  PubMed  Google Scholar 

  120. Navarro, A., Yin, P., Monsivais, D., Lin, S. M., Du, P., Wei, J. J., et al. (2012). Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PLoS One, 7(3), e33284. https://doi.org/10.1371/journal.pone.0033284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nezhat, C., King, L. P., Paka, C., Odegaard, J., & Beygui, R. (2012). Bilateral thoracic endometriosis affecting the lung and diaphragm. Journal of the Society of Laparoendoscopic Surgeons, 16(1), 140–142. https://doi.org/10.4293/108680812X13291597716384.

    Article  PubMed  Google Scholar 

  122. Nguyen, H. P. T., Xiao, L., Deane, J. A., Tan, K. S., Cousins, F. L., Masuda, H., et al. (2017). N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays. Human Reproduction, 32(11), 2254–2268. https://doi.org/10.1093/humrep/dex289.

    Article  CAS  PubMed  Google Scholar 

  123. Okolo, S. (2008). Incidence, aetiology and epidemiology of uterine fibroids. Best Practice & Research Clinical Obstetrics & Gynaecology, 22(4), 571–588.

    Article  Google Scholar 

  124. Ong, Y. R., Cousins, F. L., Yang, X., Mushafi, A., Breault, D. T., Gargett, C. E., et al. (2018). Bone marrow stem cells do not contribute to endometrial cell lineages in chimeric mouse models. Stem Cells, 36(1), 91–102. https://doi.org/10.1002/stem.2706.

    Article  CAS  PubMed  Google Scholar 

  125. Ono, M., & Maruyama, T. (2015). Stem cells in myometrial physiology. Seminars in Reproductive Medicine, 33(5), 350–356. https://doi.org/10.1055/s-0035-1563602.

    Article  CAS  PubMed  Google Scholar 

  126. Ono, M., Maruyama, T., Masuda, H., Kajitani, T., Nagashima, T., Arase, T., et al. (2007). Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(47), 18700–18705. https://doi.org/10.1073/pnas.0704472104.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Ono, M., Kajitani, T., Uchida, H., Arase, T., Oda, H., Nishikawa-Uchida, S., et al. (2010). OCT4 expression in human uterine myometrial stem/progenitor cells. Human Reproduction, 25(8), 2059–2067. https://doi.org/10.1093/humrep/deq163.

    Article  CAS  PubMed  Google Scholar 

  128. Ono, M., Qiang, W., Serna, V. A., Yin, P., Coon, J. S., Navarro, A., et al. (2012). Role of stem cells in human uterine leiomyoma growth. PLoS One, 7(5), e36935. https://doi.org/10.1371/journal.pone.0036935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ono, M., Yin, P., Navarro, A., Moravek, M. B., Coon, J. S., Druschitz, S. A., et al. (2013). Paracrine activation of WNT/beta-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 110(42), 17053–17058. https://doi.org/10.1073/pnas.1313650110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Ono, M., Kajitani, T., Uchida, H., Arase, T., Oda, H., Uchida, S., et al. (2015). CD34 and CD49f double-positive and lineage marker-negative cells isolated from human myometrium exhibit stem cell-like properties involved in pregnancy-induced uterine remodeling. Biology of Reproduction, 93(2), 37. https://doi.org/10.1095/biolreprod.114.127126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Orciani, M., Caffarini, M., Biagini, A., Lucarini, G., Delli Carpini, G., Berretta, A., et al. (2018). Chronic inflammation may enhance leiomyoma development by the involvement of progenitor cells. Stem Cells International, 2018, 1716246. https://doi.org/10.1155/2018/1716246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Othman, E. R., Elgamal, D. A., Refaiy, A. M., Abdelaal, I. I., Abdel-Mola, A. F., & Al-Hendy, A. (2016). Identification and potential role of telocytes in human uterine leiomyoma. Contraception and Reproductive Medicine, 1, 12. https://doi.org/10.1186/s40834-016-0022-5.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Pacchiarotti, A., Caserta, D., Sbracia, M., & Moscarini, M. (2011). Expression of oct-4 and c-kit antigens in endometriosis. Fertility and Sterility, 95(3), 1171–1173. https://doi.org/10.1016/j.fertnstert.2010.10.029.

    Article  CAS  PubMed  Google Scholar 

  134. Parker, W. H. (2007). Etiology, symptomatology, and diagnosis of uterine myomas. Fertility and Sterility, 87(4), 725–736. https://doi.org/10.1016/j.fertnstert.2007.01.093.

    Article  PubMed  Google Scholar 

  135. Patel, A. N., Park, E., Kuzman, M., Benetti, F., Silva, F. J., & Allickson, J. G. (2008). Multipotent menstrual blood stromal stem cells: Isolation, characterization, and differentiation. Cell Transplantation, 17(3), 303–311. https://doi.org/10.3727/096368908784153922.

    Article  PubMed  Google Scholar 

  136. Patterson, A. L., George, J. W., Chatterjee, A., Carpenter, T. J., Wolfrum, E., Chesla, D. W., et al. (2020). Putative human myometrial and fibroid stem-like cells have mesenchymal stem cell and endometrial stromal cell properties. Human Reproduction, 35(1), 44–57. https://doi.org/10.1093/humrep/dez247.

    Article  CAS  PubMed  Google Scholar 

  137. Peric, H., & Fraser, I. S. (2006). The symptomatology of adenomyosis. Best Practice & Research. Clinical Obstetrics & Gynaecology, 20(4), 547–555. https://doi.org/10.1016/j.bpobgyn.2006.01.006.

    Article  CAS  Google Scholar 

  138. Pluchino, N., Mamillapalli, R., Shaikh, S., Habata, S., Tal, A., Gaye, M., et al. (2020). CXCR4 or CXCR7 antagonists treat endometriosis by reducing bone marrow cell trafficking. Journal of Cellular and Molecular Medicine, 24(4), 2464–2474. https://doi.org/10.1111/jcmm.14933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Polyak, K., & Hahn, W. C. (2006). Roots and stems: Stem cells in cancer. Nature Medicine, 12(3), 296–300. https://doi.org/10.1038/nm1379.

    Article  CAS  PubMed  Google Scholar 

  140. Prusinski Fernung, L. E., Jones, K., Mas, A., Kleven, D., Waller, J. L., & Al-Hendy, A. (2018). Expanding upon the human myometrial stem cell hypothesis and the role of race, hormones, age, and parity in a profibroid environment. The American Journal of Pathology, 188(10), 2293–2306. https://doi.org/10.1016/j.ajpath.2018.06.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Prusinski Fernung, L. E., Al-Hendy, A., & Yang, Q. (2019). A preliminary study: Human fibroid Stro-1(+)/CD44(+) stem cells isolated from uterine fibroids demonstrate decreased DNA repair and genomic integrity compared to adjacent myometrial Stro-1(+)/CD44(+) cells. Reproductive Sciences, 26(5), 619–638. https://doi.org/10.1177/1933719118783252.

    Article  CAS  PubMed  Google Scholar 

  142. Rakhila, H., Al-Akoum, M., Bergeron, M. E., Leboeuf, M., Lemyre, M., Akoum, A., et al. (2016). Promotion of angiogenesis and proliferation cytokines patterns in peritoneal fluid from women with endometriosis. Journal of Reproductive Immunology, 116, 1–6. https://doi.org/10.1016/j.jri.2016.01.005.

    Article  CAS  PubMed  Google Scholar 

  143. Ramirez Williams, L., Bruggemann, K., Hubert, M., Achmad, N., Kiesel, L., Schafer, S. D., et al. (2019). Gamma-secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells. Acta Obstetricia et Gynecologica Scandinavica, 98(12), 1565–1574. https://doi.org/10.1111/aogs.13707.

    Article  CAS  PubMed  Google Scholar 

  144. Ratajczak, M. Z., Zuba-Surma, E., Wojakowski, W., Suszynska, M., Mierzejewska, K., Liu, R., et al. (2014). Very small embryonic-like stem cells (VSELs) represent a real challenge in stem cell biology: Recent pros and cons in the midst of a lively debate. Leukemia, 28(3), 473–484. https://doi.org/10.1038/leu.2013.255.

    Article  CAS  PubMed  Google Scholar 

  145. Renema, N., Navet, B., Heymann, M. F., Lezot, F., & Heymann, D. (2016). RANK-RANKL signalling in cancer. Bioscience Reports, 36(4). https://doi.org/10.1042/BSR20160150.

  146. Ripps, B. A., & Martin, D. C. (1991). Focal pelvic tenderness, pelvic pain and dysmenorrhea in endometriosis. The Journal of Reproductive Medicine, 36(7), 470–472.

    CAS  PubMed  Google Scholar 

  147. Rossignoli, F., Caselli, A., Grisendi, G., Piccinno, S., Burns, J. S., Murgia, A., et al. (2013). Isolation, characterization, and transduction of endometrial decidual tissue multipotent mesenchymal stromal/stem cells from menstrual blood. BioMed Research International, 2013, 901821. https://doi.org/10.1155/2013/901821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sakr, S., Naqvi, H., Komm, B., & Taylor, H. S. (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(4), 1489–1497. https://doi.org/10.1210/en.2013-1977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Santamaria, X., Massasa, E. E., Feng, Y., Wolff, E., & Taylor, H. S. (2011). Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes. Molecular Therapy, 19(11), 2065–2071. https://doi.org/10.1038/mt.2011.173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Santamaria, X., Massasa, E. E., & Taylor, H. S. (2012). Migration of cells from experimental endometriosis to the uterine endometrium. Endocrinology, 153(11), 5566–5574. https://doi.org/10.1210/en.2012-1202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Santamaria, X., Cabanillas, S., Cervello, I., Arbona, C., Raga, F., Ferro, J., et al. (2016). Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman’s syndrome and endometrial atrophy: A pilot cohort study. Human Reproduction, 31(5), 1087–1096. https://doi.org/10.1093/humrep/dew042.

    Article  CAS  PubMed  Google Scholar 

  152. Sarma, D., Iyengar, P., Marotta, T. R., KG, T. B., Gentili, F., & Halliday, W. (2004). Cerebellar endometriosis. The American Journal of Roentgenology, 182(6), 1543–1546. https://doi.org/10.2214/ajr.182.6.1821543.

    Article  PubMed  Google Scholar 

  153. Schuring, A. N., Dahlhues, B., Korte, A., Kiesel, L., Titze, U., Heitkotter, B., et al. (2018). The endometrial stem cell markers notch-1 and numb are associated with endometriosis. Reproductive Biomedicine Online, 36(3), 294–301. https://doi.org/10.1016/j.rbmo.2017.11.010.

    Article  CAS  PubMed  Google Scholar 

  154. Schwab, K. E., & Gargett, C. E. (2007). Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Human Reproduction, 22(11), 2903–2911. https://doi.org/10.1093/humrep/dem265.

    Article  CAS  PubMed  Google Scholar 

  155. Seaberg, R. M., & van der Kooy, D. (2003). Stem and progenitor cells: The premature desertion of rigorous definitions. Trends in Neurosciences, 26(3), 125–131. https://doi.org/10.1016/S0166-2236(03)00031-6.

    Article  CAS  PubMed  Google Scholar 

  156. Shalaby, S. M., Khater, M. K., Perucho, A. M., Mohamed, S. A., Helwa, I., Laknaur, A., et al. (2016). Magnetic nanoparticles as a new approach to improve the efficacy of gene therapy against differentiated human uterine fibroid cells and tumor-initiating stem cells. Fertility and Sterility, 105(6), 1638–1648 e8. https://doi.org/10.1016/j.fertnstert.2016.03.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Shariati, F., Favaedi, R., Ramazanali, F., Ghoraeian, P., Afsharian, P., Aflatoonian, B., et al. (2018). Increased expression of stemness genes REX-1, OCT-4, NANOG, and SOX-2 in women with ovarian endometriosis versus normal endometrium: A case-control study. International Journal of Reproductive BioMedicine (Yazd), 16(12). https://doi.org/10.18502/ijrm.v16i12.3684.

  158. Shoae-Hassani, A., Sharif, S., Seifalian, A. M., Mortazavi-Tabatabaei, S. A., Rezaie, S., & Verdi, J. (2013). Endometrial stem cell differentiation into smooth muscle cell: A novel approach for bladder tissue engineering in women. BJU International, 112(6), 854–863. https://doi.org/10.1111/bju.12195.

    Article  CAS  PubMed  Google Scholar 

  159. Shoae-Hassani, A., Mortazavi-Tabatabaei, S. A., Sharif, S., Seifalian, A. M., Azimi, A., Samadikuchaksaraei, A., et al. (2015). Differentiation of human endometrial stem cells into urothelial cells on a three-dimensional nanofibrous silk-collagen scaffold: An autologous cell resource for reconstruction of the urinary bladder wall. Journal of Tissue Engineering and Regenerative Medicine, 9(11), 1268–1276. https://doi.org/10.1002/term.1632.

    Article  CAS  PubMed  Google Scholar 

  160. Shynlova, O., Kwong, R., & Lye, S. J. (2010). Mechanical stretch regulates hypertrophic phenotype of the myometrium during pregnancy. Reproduction, 139(1), 247–253. https://doi.org/10.1530/REP-09-0260.

    Article  CAS  PubMed  Google Scholar 

  161. Sidney, L. E., Branch, M. J., Dunphy, S. E., Dua, H. S., & Hopkinson, A. (2014). Concise review: Evidence for CD34 as a common marker for diverse progenitors. Stem Cells, 32(6), 1380–1389. https://doi.org/10.1002/stem.1661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Singh, P., & Bhartiya, D. (2020). Pluripotent stem (VSELs) and progenitor (EnSCs) cells exist in adult mouse uterus and show cyclic changes across estrus cycle. Reproductive Sciences. https://doi.org/10.1007/s43032-020-00250-2.

  163. Singh, S., Singh, U. P., Grizzle, W. E., & Lillard, J. W., Jr. (2004). CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion. Laboratory Investigation, 84(12), 1666–1676. https://doi.org/10.1038/labinvest.3700181.

    Article  CAS  PubMed  Google Scholar 

  164. Singh, N., Mohanty, S., Seth, T., Shankar, M., Bhaskaran, S., & Dharmendra, S. (2014). Autologous stem cell transplantation in refractory Asherman’s syndrome: A novel cell based therapy. The Journal of Human Reproductive Sciences, 7(2), 93–98. https://doi.org/10.4103/0974-1208.138864.

    Article  PubMed  Google Scholar 

  165. Snykers, S., De Kock, J., Rogiers, V., & Vanhaecke, T. (2009). In vitro differentiation of embryonic and adult stem cells into hepatocytes: State of the art. Stem Cells, 27(3), 577–605. https://doi.org/10.1634/stemcells.2008-0963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Spencer, T. E., Hayashi, K., Hu, J., & Carpenter, K. D. (2005). Comparative developmental biology of the mammalian uterus. Current Topics in Developmental Biology, 68, 85–122. https://doi.org/10.1016/S0070-2153(05)68004-0.

    Article  CAS  PubMed  Google Scholar 

  167. Spitzer, T. L., Rojas, A., Zelenko, Z., Aghajanova, L., Erikson, D. W., Barragan, F., et al. (2012). Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype. Biology of Reproduction, 86(2), 58. https://doi.org/10.1095/biolreprod.111.095885.

    Article  CAS  PubMed  Google Scholar 

  168. Sugawara, K., Hamatani, T., Yamada, M., Ogawa, S., Kamijo, S., Kuji, N., et al. (2014). Derivation of human decidua-like cells from amnion and menstrual blood. Scientific Reports, 4, 4599. https://doi.org/10.1038/srep04599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Taghizadeh, M., & Noruzinia, M. (2017). Lovastatin reduces stemness via epigenetic reprograming of BMP2 and GATA2 in human endometrium and endometriosis. Cell Journal, 19(1), 50–64. https://doi.org/10.22074/cellj.2016.3894.

    Article  PubMed  Google Scholar 

  170. Tan, J., Li, P., Wang, Q., Li, Y., Li, X., Zhao, D., et al. (2016). Autologous menstrual blood-derived stromal cells transplantation for severe Asherman’s syndrome. Human Reproduction, 31(12), 2723–2729. https://doi.org/10.1093/humrep/dew235.

    Article  PubMed  Google Scholar 

  171. Tanwar, P. S., Lee, H. J., Zhang, L., Zukerberg, L. R., Taketo, M. M., Rueda, B. R., et al. (2009). Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biology of Reproduction, 81(3), 545–552. https://doi.org/10.1095/biolreprod.108.075648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Taylor, H. S. (2004). Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA, 292(1), 81–85. https://doi.org/10.1001/jama.292.1.81.

    Article  CAS  PubMed  Google Scholar 

  173. Teixeira, J., Rueda, B. R., & Pru, J. K. (2008). Uterine stem cells. Cambridge, MA: StemBook.

    Book  Google Scholar 

  174. Townsend, D. E., Sparkes, R. S., Baluda, M. C., & McClelland, G. (1970). Unicellular histogenesis of uterine leiomyomas as determined by electrophoresis by glucose-6-phosphate dehydrogenase. American Journal of Obstetrics and Gynecology, 107(8), 1168–1173.

    Article  CAS  Google Scholar 

  175. Triolo, O., Lagana, A. S., & Sturlese, E. (2013). Chronic pelvic pain in endometriosis: An overview. Journal of Clinical Medical Research, 5(3), 153–163. https://doi.org/10.4021/jocmr1288w.

    Article  CAS  Google Scholar 

  176. Tsuji, S., Yoshimoto, M., Takahashi, K., Noda, Y., Nakahata, T., & Heike, T. (2008). Side population cells contribute to the genesis of human endometrium. Fertility and Sterility, 90(4 Suppl), 1528–1537. https://doi.org/10.1016/j.fertnstert.2007.08.005.

    Article  PubMed  Google Scholar 

  177. Valentijn, A. J., Palial, K., Al-Lamee, H., Tempest, N., Drury, J., Von Zglinicki, T., 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(10), 2695–2708. https://doi.org/10.1093/humrep/det285.

    Article  CAS  PubMed  Google Scholar 

  178. Vannuccini, S., Tosti, C., Carmona, F., Huang, S. J., Chapron, C., Guo, S. W., et al. (2017). Pathogenesis of adenomyosis: An update on molecular mechanisms. Reproductive Biomedicine Online, 35(5), 592–601. https://doi.org/10.1016/j.rbmo.2017.06.016.

    Article  CAS  PubMed  Google Scholar 

  179. Velagaleti, G. V., Tonk, V. S., Hakim, N. M., Wang, X., Zhang, H., Erickson-Johnson, M. R., et al. (2010). Fusion of HMGA2 to COG5 in uterine leiomyoma. Cancer Genetics and Cytogenetics, 202(1), 11–16. https://doi.org/10.1016/j.cancergencyto.2010.06.002.

    Article  CAS  PubMed  Google Scholar 

  180. Walker, C. L., & Stewart, E. A. (2005). Uterine fibroids: The elephant in the room. Science, 308(5728), 1589–1592.

    Article  CAS  Google Scholar 

  181. Wang, L., Wang, L., Gu, Y., Shu, Y., Shen, Y., & Xu, Q. (2011). Integrin alpha6(high) cell population functions as an initiator in tumorigenesis and relapse of human liposarcoma. Molecular Cancer Therapeutics, 10(12), 2276–2286. https://doi.org/10.1158/1535-7163.MCT-11-0487.

    Article  CAS  PubMed  Google Scholar 

  182. Wang, J., Chen, S., Zhang, C., Stegeman, S., Pfaff-Amesse, T., Zhang, Y., et al. (2012). Human endometrial stromal stem cells differentiate into megakaryocytes with the ability to produce functional platelets. PLoS One, 7(8), e44300. https://doi.org/10.1371/journal.pone.0044300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Wang, X., Mamillapalli, R., Mutlu, L., Du, H., & Taylor, H. S. (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(1), 14–22. https://doi.org/10.1016/j.scr.2015.04.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Watt, F. M., & Hogan, B. L. (2000). Out of Eden: Stem cells and their niches. Science, 287(5457), 1427–1430. https://doi.org/10.1126/science.287.5457.1427.

    Article  CAS  PubMed  Google Scholar 

  185. Wei, L. H., Torng, P. L., Hsiao, S. M., Jeng, Y. M., Chen, M. W., & Chen, C. A. (2011). Histone deacetylase 6 regulates estrogen receptor alpha in uterine leiomyoma. Reproductive Sciences, 18(8), 755–762. https://doi.org/10.1177/1933719111398147.

    Article  CAS  PubMed  Google Scholar 

  186. Wolff, E. F., Gao, X. B., Yao, K. V., Andrews, Z. B., Du, H., Elsworth, J. D., et al. (2011). Endometrial stem cell transplantation restores dopamine production in a Parkinson’s disease model. Journal of Cellular and Molecular Medicine, 15(4), 747–755. https://doi.org/10.1111/j.1582-4934.2010.01068.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Yamagata, Y., Maekawa, R., Asada, H., Taketani, T., Tamura, I., Tamura, H., et al. (2009). Aberrant DNA methylation status in human uterine leiomyoma. Molecular Human Reproduction, 15(4), 259–267. https://doi.org/10.1093/molehr/gap010.

    Article  CAS  PubMed  Google Scholar 

  188. Yang, Q., & Al-Hendy, A. (2016). Developmental environmental exposure alters the epigenetic features of myometrial stem cells. Gynecology and Obstetrics Research, 3(2), e1–e4. https://doi.org/10.17140/GOROJ-3-e005.

    Article  PubMed  Google Scholar 

  189. Yang, J. H., Wu, M. Y., Chen, M. J., Chen, S. U., Yang, Y. S., & Ho, H. N. (2009). Increased matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 secretion but unaffected invasiveness of endometrial stromal cells in adenomyosis. Fertility and Sterility, 91(5 Suppl), 2193–2198. https://doi.org/10.1016/j.fertnstert.2008.05.090.

    Article  CAS  PubMed  Google Scholar 

  190. Yin, P., Ono, M., Moravek, M. B., Coon, J. S., Navarro, A., Monsivais, D., et al. (2015). Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo. The Journal of Clinical Endocrinology and Metabolism, 100(4), E601–E606. https://doi.org/10.1210/jc.2014-2134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Yu, D., Wong, Y. M., Cheong, Y., Xia, E., & Li, T. C. (2008). Asherman syndrome – one century later. Fertility and Sterility, 89(4), 759–779. https://doi.org/10.1016/j.fertnstert.2008.02.096.

    Article  PubMed  Google Scholar 

  192. Zanette, D. L., Lorenzi, J. C., Panepucci, R. A., Palma, P. V., Dos Santos, D. F., Prata, K. L., et al. (2015). Simvastatin modulates mesenchymal stromal cell proliferation and gene expression. PLoS One, 10(4), e0120137. https://doi.org/10.1371/journal.pone.0120137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zavadil, J., Ye, H., Liu, Z., Wu, J., Lee, P., Hernando, E., et al. (2010). Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas. PLoS One, 5(8), e12362. https://doi.org/10.1371/journal.pone.0012362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Zeng, B., Hu, J., Yuan, R., Hu, L., Zhong, L., & Kang, K. (2012). Increased expression of importin13 in endometriosis and endometrial carcinoma. Medical Science Monitor, 18(6), CR361–CR367. https://doi.org/10.12659/msm.882879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Zeybek, B., Costantine, M., Kilic, G. S., & Borahay, M. A. (2018). Therapeutic roles of statins in gynecology and obstetrics: The current evidence. Reproductive Sciences, 1933719117750751. https://doi.org/10.1177/1933719117750751.

  196. Zhang, Z., Wang, J., Chen, Y., Suo, L., Chen, H., Zhu, L., et al. (2019). Activin a promotes myofibroblast differentiation of endometrial mesenchymal stem cells via STAT3-dependent Smad/CTGF pathway. Cell Communication and Signaling: CCS, 17(1), 45. https://doi.org/10.1186/s12964-019-0361-3.

    Article  CAS  Google Scholar 

  197. Zhang, W., Li, X., Li, H., Lu, X., Chen, J., Li, L., et al. (2020). 17beta-estradiol promotes bone marrow mesenchymal stem cell migration mediated by chemokine upregulation. Biochemical and Biophysical Research Communications. https://doi.org/10.1016/j.bbrc.2020.07.135.

Download references

Funding

This work was supported, in part, by NIH grant 1R01HD094380-01 to Mostafa A. Borahay.

Author information

Authors and Affiliations

  1. Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Malak El Sabeh, Sadia Afrin, Bhuchitra Singh, Mariko Miyashita-Ishiwata & Mostafa Borahay

Authors
  1. Malak El Sabeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sadia Afrin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bhuchitra Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariko Miyashita-Ishiwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mostafa Borahay
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Malak El Sabeh and Sadia Afrin performed the literature search and drafted the manuscript. Bhuchitra Singh, Mariko Miyashita-Ishiwata, and Mostafa Borahay contributed to the writing and critically revised the work.

Corresponding author

Correspondence to Mostafa Borahay.

Ethics declarations

Conflict of Interest

The authors have no conflicts of interest to declare that are relevant to the content of this article.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El Sabeh, M., Afrin, S., Singh, B. et al. Uterine Stem Cells and Benign Gynecological Disorders: Role in Pathobiology and Therapeutic Implications. Stem Cell Rev and Rep 17, 803–820 (2021). https://doi.org/10.1007/s12015-020-10075-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-020-10075-w

Keywords

Search

Navigation