CELL TECHNOLOGIES FOR ENDOMETRIOSIS PATHOGENESIS STUDY

DOI: https://doi.org/10.29296/24999490-2022-05-02

E.V. Okladnikova, T.G. Ruksha
Professor V. F. Voino-Yasenetsky Krasnoyarsk State Medical University,
Partizana Zheleznyaka str., 1, Krasnoyarsk, 660022, Russian Federation

Introduction. Endometriosis is a chronic inflammatory estrogen-dependent disease characterized by the presence of endometrial tissue outside the uterine cavity. The pathogenesis of endometriosis is not fully determined. The relevance of its study is due to the development of chronic inflammation in the lesions, which is accompanied by a pronounced pain syndrome. The appearance of ectopic foci in the reproductive system of women of fertile age can lead to the development of infertility. Animals or cell cultures can be used to study the pathogenesis of the disease. The aim of the study. To summarize the current data on the possibilities of modeling endometriosis using cell cultures, to consider the features of different models and their application to study the pathogenesis of the disease. Methods. The materials were the results of research on this topic over the past 20 years, from 2002 to 2022. The publications included in the databases «Pubmed», «Medline», «eLibrary.ru «. Results. This review provides information about the advantages and disadvantages of endometriosis modeling in vivo and in vitro. In animals, the initiation of the disease is impossible in a natural way (with the exception of primates), they require maintenance costs, their use is limited by ethical standards. Among the cell cultures used to study endometriosis, monocultures (stromal, epithelial, stem, mesothelial, immune cells) and co-cultures can be distinguished. The choice of the model is determined by the objectives of the study. The review presents some features of cell isolation from ectopic endometrial tissue, methods of cell identification and methods of their cultivation. The use of immortalized cell lines and 3D models in the study of the pathogenesis of the disease is discussed. Conclusion. Modeling of endometriosis has a number of technological problems due to both the nature of the disease and the biological properties of cells involved in the pathogenesis of endometriosis. Compared to animal models, in vitro models allow easy access to target cells to identify critical cellular and molecular factors, and to evaluate intercellular interactions that contribute to the development of the disease
Keywords: 
endometriosis, in vitro, cell cultures, pathogenesis

Список литературы: 
  1. Taylor H.S., Kotlyar A.M., Flores V.A. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021; 397 (10276): 839–52. DOI: 10.1016/S0140-6736(21)00389-5.
  2. Saunders P.T.K, Horne A.W. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021; 184 (11): 2807–24. DOI: 10.1016/j.cell.2021.04.041.
  3. Anglesio M.S., Bashashati A., Wang Y.K., Senz J., Ha G., Yang W., Aniba M.R., Prentice L.M., Farahani H, Li Chang H., Karnezis A.N., Marra M.A., Yong P.J., Hirst M., Gilks B., Shah S.P., Huntsman D.G. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. J. Pathol. 2015; 236 (2): 201–9. DOI: 10.1002/path.4516.
  4. Dongxu Z., Fei Y., Xing X., Bo-Yin Z., Qingsan Z. Low back pain tied to spinal endometriosis. Eur Spine J. 2014; 23 (2): 214–7. DOI: 10.1007/s00586-013-2988-x.
  5. Bulun S.E., Yilmaz B.D., Sison C., Miyazaki K., Bernardi L., Liu S., Kohlmeier A., Yin P., Milad M., Wei J. Endometriosis. Endocr Rev. 2019; 40 (4): 1048–79. DOI: 10.1210/er.2018-00242.
  6. Suda K., Nakaoka H., Yoshihara K., Ishiguro T., Tamura R., Mori Y., Yamawaki K., Adachi S., Takahashi T., Kase H., Tanaka K., Yamamoto T., Motoyama T., Inoue I., Enomoto T. Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium. Cell Rep. 2018; 24 (7): 1777–89. DOI: 10.1016/j.celrep.2018.07.037.
  7. Burns K.A., Pearson A.M., Slack J.L., Por E.D., Scribner A.N., Eti N.A., Burney R.O. Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model. Front Physiol. 2022; 12: 806574. DOI: 10.3389/fphys.2021.806574.
  8. Cuevas M., Cruz M.L., Ramirez A.E., Flores I., Thompson K.J., Bayona M., Vernon M.W., Appleyard C.B. Stress During Development of Experimental Endometriosis Influences Nerve Growth and Disease Progression. Reprod Sci. 2018; 25 (3): 347–57. DOI: 10.1177/1933719117737846.
  9. Malvezzi H., Marengo E.B., Podgaec S., Piccinato C.A. Endometriosis: current challenges in modeling a multifactorial disease of unknown etiology. J Transl Med. 2020; 18 (1): 311. DOI: 10.1186/s12967-020-02471-0.
  10. Brasted M., White C.A., Kennedy T.G., Salamonsen L.A. Mimicking the events of menstruation in the murine uterus. Biol Reprod. 2003; 69 (4): 1273–80. DOI: 10.1095/biolreprod.103.016550.
  11. Greaves E., Cousins F.L., Murray A., Esnal-Zufiaurre A., Fassbender A., Horne A.W., Saunders P.T. A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. Am. J. Pathol. 2014; 184 (7): 1930–9. DOI: 10.1016/j.ajpath.2014.03.011.
  12. Szegeczki V., Fazekas L., Kulcsár M., Reglodi D., Török P., Orlik B., Laganà A.S., Jakab A., Juhasz T. Endometrium as Control of Endometriosis in Experimental Research: Assessment of Sample Suitability. Diagnostics (Basel). 2022; 12 (4): 970. DOI: 10.3390/diagnostics12040970.
  13. Greaves E., Critchley H.O.D., Horne A.W., Saunders P.T.K. Relevant human tissue resources and laboratory models for use in endometriosis research. Acta Obstet Gynecol Scand. 2017; 96 (6): 644–58. DOI: 10.1111/aogs.13119.
  14. Павлович С.В., Кречетова Л.В., Вторушина В.В., Ванько Л.В., Мелкумян А.Г., Юшина М.Н., Савилова А.М., Макиян З.Н., Яроцкая Е.Л., Хилькевич Е.Г., Чупрынин В.Д., Сухих Г.Т. Особенности профиля секретируемых белков клетками из эндометриоидных очагов и эутопического эндометрия женщин с наружным генитальным эндометриозом в культуре in vitro. Акушерство и гинекология. 2019; 8: 90–9. DOI: 10.18565/aig.2019.8.90-99. [Pavlovich Stanislav V. Krechetova L.V. Vtorushina Valentina V. Vanko L.V., Melkumyan A.G., Yushina M.N., Savilova Anastasia M., Makiyanzograb N., Yarotskaya Ekaterina L. Khilkevich Elena G., Chuprynin Vladimir D., Sykhikh Gennady T. Features of the profile of proteins secreted by cells from the endometrioid foci and eutopic endometrium in women with external genital endometriosis in vitro culture. Obstetrics and Gynecology. 2019; 8: 90–9 (in Russian)]
  15. Zhou C.F., Liu M.J., Wang W., Wu S., Huang Y.X., Chen G.B., Liu L.M., Peng D.X., Wang X.F., Cai X.Z., Li X.X., Feng W.Q., Ma Y. miR-205-5p inhibits human endometriosis progression by targeting ANGPT2 in endometrial stromal cells. Stem Cell Res Ther. 2019; 10 (1): 287. DOI: 10.1186/s13287-019-1388-5.
  16. Zhang Y., Yan J., Pan X. miR-141-3p affects apoptosis and migration of endometrial stromal cells by targeting KLF-12. Pflugers Arch. 2019; 471 (8): 1055–63. DOI: 10.1007/s00424-019-02283-2.
  17. Shen L., Hong X., Liu Y., Zhou W., Zhang Y. The miR-25-3p/Sp1 pathway is dysregulated in ovarian endometriosis. J. Int. Med. Res. 2020; 48 (4): 300060520918437. DOI: 10.1177/0300060520918437.
  18. Choi J., Jo M., Lee E., Lee D.Y., Choi D. Involvement of endoplasmic reticulum stress in regulation of endometrial stromal cell invasiveness: possible role in pathogenesis of endometriosis. Mol. Hum Reprod. 2019; 25 (3): 101–10. DOI: 10.1093/molehr/gaz002.
  19. Choi J., Jo M., Lee E., Lee D.Y., Choi D. Nuclear factor-kappa B signaling in endometriotic stromal cells is not inhibited by progesterone owing to an aberrant endoplasmic reticulum stress response: a possible role for an altered inflammatory process in endometriosis. Mol Hum Reprod. 2021; 27 (2): gaab002. DOI: 10.1093/molehr/gaab002.
  20. Клейменова Т.С., Дробинцева А.О., Полякова В.О., Крылова Ю.С., Цыпурдеева А.А. Эндометриальная культура человека: инвазионные свойства. Репродуктивная медицина. 2019; 1 (38): 19–24. [Kleimenova T.S., Drobintseva A.O., Polyakova V.O., Krylova I.S., Tsipurdieva A.A. Endometrium culture of the human: research of invasive. Reproductive medicine. 2019; 1 (38): 19–24 (in Russian)]
  21. Kolahdouz-Mohammadi R., Shidfar F., Khodaverdi S., Arablou T., Heidari S., Rashidi N., Delbandi A.A. Resveratrol treatment reduces expression of MCP-1, IL-6, IL-8 and RANTES in endometriotic stromal cells. J. Cell. Mol. Med. 2021; 25 (2): 1116–27. DOI: 10.1111/jcmm.16178.
  22. Hung S.W., Liang B., Gao Y., Zhang R., Tan Z., Zhang T., Chung P.W.J., Chan T.H., Wang C.C. An In-Silico, In-Vitro and In-Vivo Combined Approach to Identify NMNATs as Potential Protein Targets of ProEGCG for Treatment of Endometriosis. Front Pharmacol. 2021; 12: 714790. DOI: 10.3389/fphar.2021.714790.
  23. Huang R., Chen S., Zhao M., Li Z., Zhu L. Ginsenoside Rg3 attenuates endometriosis by inhibiting the viability of human ectopic endometrial stromal cells through the nuclear factor-kappaB signaling pathway. Jю Gynecol Obstet Hum Reprod. 2020; 49 (1): 101642. DOI: 10.1016/j.jogoh.2019.101642.
  24. Wang Y., Nicholes K., Shih I.M. The Origin and Pathogenesis of Endometriosis. Annu Rev Pathol. 2020; 15: 71–95. DOI: 10.1146/annurev-pathmechdis-012419-032654.
  25. Kong Y., Shao Y., Ren C., Yang G. Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis. Stem Cell Res Ther. 2021; 12 (1): 474. DOI: 10.1186/s13287-021-02526-z.
  26. Gil-Sanchis C., Cervelló I., Mas A., Faus A., Pellicer A., Simón C. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) as a putative human endometrial stem cell marker. Mol Hum Reprod. 2013; 19 (7): 407–14. DOI: 10.1093/molehr/gat014.
  27. El Sabeh M., Afrin S., Singh B., Miyashita-Ishiwata M., Borahay M. Uterine Stem Cells and Benign Gynecological Disorders: Role in Pathobiology and Therapeutic Implications. Stem Cell Rev Rep. 2021; 17 (3): 803–20. DOI: 10.1007/s12015-020-10075-w.
  28. Землелько В.И., Гринчук ТМ, Домнина А.П., Арцыбашева И.В., Зенин В.В., Кирсанов А.А., Бичевая НК, Корсак В.С., Никольский Н.Н. Мультипотентные мезенхимные стволовые клетки десквамированного эндометрия. Выделение, характеристика и использование в качестве фидерного слоя для культивирования эмбриональных стволовых линий человека. Цитология. 2011; 53 (12): 919–29. [Zemelko V.I., Grinchuk T.M., Domnina A.P., Artzibasheva I.V., Zenin V.V., Kirsanov A.A., Bichevaia N.K., Korsak V.S., Nikolsky N.N. Multipotent mesenchymal stem cells of desquamated endometrium. Isolation, characterization, and application as a feeder layer for maintenance of human embryonic stem cells. Reproductive medicine. 2011; 53 (12): 919–29 (in Russian)]
  29. Ikoma T., Kyo S., Maida Y., Ozaki S., Takakura M., Nakao S., Inoue M. Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. Am. J. Obstet Gynecol. 2009; 201 (6): 608. e1-8. DOI: 10.1016/j.ajog.2009.07.026.
  30. Du H., Taylor H.S. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007; 25 (8): 2082–6. DOI: 10.1634/stemcells.2006-0828.
  31. Young V.J., Brown J.K., Saunders P.T., Horne A.W. The role of the peritoneum in the pathogenesis of endometriosis. Hum Reprod Update. 2013; 19 (5): 558–69. DOI: 10.1093/humupd/dmt024.
  32. Young V.J., Ahmad S.F., Brown J.K., Duncan W.C., Horne A.W. ID2 mediates the transforming growth factor-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis. Mol Hum Reprod. 2016; 22 (9): 648–54. DOI: 10.1093/molehr/gaw045.
  33. Lucidi R.S., Witz C.A., Chrisco M., Binkley P.A., Shain S.A., Schenken R.S. A novel in vitro model of the early endometriotic lesion demonstrates that attachment of endometrial cells to mesothelial cells is dependent on the source of endometrial cells. Fertil Steril. 2005; 84 (1): 16–21. DOI: 10.1016/j.fertnstert.2004.10.058.
  34. Chen Z., Dai Y., Dong Z., Li M., Mu X., Zhang R., Wang Z., Zhang W., Lang J., Leng J., Jiang X. Co-cultured endometrial stromal cells and peritoneal mesothelial cells for an in vitro model of endometriosis. Integr Biol (Camb). 2012; 4 (9): 1090–5. DOI: 10.1039/c2ib00172a.
  35. Hogg C., Horne A.W., Greaves E. Endometriosis-Associated Macrophages: Origin, Phenotype, and Function. Front Endocrinol (Lausanne). 2020; 11: 7. DOI: 10.3389/fendo.2020.00007.
  36. Hogg C., Panir K., Dhami P., Rosser M., Mack M., Soong D., Pollard J.W., Jenkins S.J., Horne A.W., Greaves E. Macrophages inhibit and enhance endometriosis depending on their origin. Proc Natl Acad Sci USA. 2021; 118 (6): e2013776118. DOI: 10.1073/pnas.2013776118.
  37. Mei J., Chang K.K., Sun H.X. Immunosuppressive macrophages induced by IDO1 promote the growth of endometrial stromal cells in endometriosis. Mol Med Rep. 2017; 15 (4): 2255–60. DOI: 10.3892/mmr.2017.6242.
  38. Chan R.W.S, Lee C.L., Ng E.H.Y, Yeung W.S.B. Co-culture with macrophages enhances the clonogenic and invasion activity of endometriotic stromal cells. Cell Prolif. 2017; 50 (3): e12330. DOI: 10.1111/cpr.12330.
  39. Huang Z.X., Wu R.F., Mao X.M., Huang S.M., Liu T.T., Chen Q.H., Chen Q.X. Establishment of an immortalized stromal cell line derived from human Endometriotic lesion. Reprod Biol Endocrinol. 2020; 18 (1): 119. DOI: 10.1186/s12958-020-00669-x.
  40. Park Y., Jung J.G., Yu Z.C., Asaka R., Shen W., Wang Y., Jung W.H., Tomaszewski A., Shimberg G., Chen Y., Parimi V., Gaillard S., Shih I.M., Wang T.L. A novel human endometrial epithelial cell line for modeling gynecological diseases and for drug screening. Lab Invest. 2021; 101 (11): 1505–12. DOI: 10.1038/s41374-021-00624-3.
  41. Banu S.K., Lee J., Starzinski-Powitz A., Arosh J.A. Gene expression profiles and functional characterization of human immortalized endometriotic epithelial and stromal cells. Fertil Steril. 2008; 90 (4): 972–87. DOI: 10.1016/j.fertnstert.2007.07.1358.
  42. Fan H. In-vitro models of human endometriosis. Exp Ther Med. 2020; 19 (3): 1617–25. DOI: 10.3892/etm.2019.8363.
  43. Ramirez R.D., Sheridan S., Girard L., Sato M., Kim Y., Pollack J., Peyton M., Zou Y., Kurie J.M., Dimaio J.M., Milchgrub S., Smith A.L., Souza R.F., Gilbey L., Zhang X., Gandia K., Vaughan M.B., Wright W.E., Gazdar A.F., Shay J.W., Minna J.D. Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res. 2004; 64 (24): 9027–34. DOI: 10.1158/0008-5472.CAN-04-3703.
  44. Sato M., Shay J.W., Minna J.D. Immortalized normal human lung epithelial cell models for studying lung cancer biology. Respir Investig. 2020; 58 (5): 344–54. DOI: 10.1016/j.resinv.2020.04.005.
  45. Esfandiari N., Ai J., Nazemian Z., Javed M.H., Gotlieb L., Casper R.F. Expression of glycodelin and cyclooxygenase-2 in human endometrial tissue following three-dimensional culture. Am. J. Reprod Immunol. 2007; 57 (1): 49–54. DOI: 10.1111/j.1600-0897.2006.00445.x.
  46. Duval K., Grover H., Han L.H., Mou Y., Pegoraro A.F., Fredberg J., Chen Z. Modeling Physiological Events in 2D vs. 3D Cell Culture. Physiology (Bethesda). 2017; 32 (4): 266–77. DOI: 10.1152/physiol.00036.2016.
  47. Gnecco J.S., Pensabene V., Li D.J., Ding T., Hui E.E., Bruner-Tran K.L., Osteen K.G. Compartmentalized Culture of Perivascular Stroma and Endothelial Cells in a Microfluidic Model of the Human Endometrium. Ann Biomed Eng. 2017; 45 (7): 1758–69. DOI: 10.1007/s10439-017-1797-5.