Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Research Article

The Biological Characteristics of Eutopic and Ectopic Endometrial Progenitor Cells in Endometriosis

Author(s): Qingxia Zhang, Jing Liang, Dongkui Xu, Ting Gao, Jinku Zhang, Haiyan Liang, Wenhui Wang, Bin Ling and Dingqing Feng*

Volume 18, Issue 8, 2023

Published on: 13 February, 2023

Page: [1172 - 1183] Pages: 12

DOI: 10.2174/1574888X18666230203162452

Price: $65

Abstract

Aim: The aim of this study was to identify the biological characteristics and potential roles of endometrial progenitor cells in the pathogenesis of endometriosis.

Background: It is generally believed that progenitor cells in human endometrium are responsible for rapid endometrial regeneration. However, the biological characteristics and potential roles of the paired eutopic and ectopic endometrial progenitor cells in endometriosis remain unclear.

Objective: This study intends to isolate the epithelial progenitor (EP) cells and endometrial mesenchymal stem cells (eMSCs) from the eutopic and ectopic endometria from endometriosis patients, further to reveal their features and functions respectively.

Methods: The distributions of EP cells and eMSCs and the expression of steroid hormone receptors in the endometrium and endometriotic tissues were assessed by immunohistochemistry. EP cells and eMSCs were sorted from paired eutopic and ectopic endometria with epithelial cell adhesion molecule (EpCAM) magnetic beads. The clonogenicity, cell viability after being treated with estradiol and progesterone, and cell markers expression were evaluated with colony forming on Matrigel, CCK-8 and immunofluorescence staining, respectively. The differentially expressed genes (DEGs) were further identified with RNA sequencing.

Results: SSEA-1- and PDGFRβ-positive cells were distributed in the epithelial and stromal layers. The ERβ staining was much more intense in endometriotic tissues, but PR expression was almost absent. The ectopic EP cells exhibit strong clonogenicity and ERβ expression but weak PR expression, leading to progesterone resistance. There are 12604 and 13242 DEGs revealed by RNA sequencing between eutopic and ectopic EP cells or eMSCs. GO and KEGG analyses revealed that the functions and pathways of DEGs enriched in cellular energy metabolism and regulation of the immune response, respectively. Additionally, ERβ targets were mainly enriched in ectopic EP cells.

Conclusion: Both EP cells and eMSCs may engage in ectopic lesion formation in endometriosis by modifying the metabolic mode and immune tolerance. These data not only help to understand the molecular mechanism of endometriosis but also could potentially contribute to the discovery of therapeutic targets for endometriosis.

Graphical Abstract

[1]
Nguyen HPT, Xiao L, Deane JA, et al. N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays. Hum Reprod 2017; 32(11): 2254-68.
[http://dx.doi.org/10.1093/humrep/dex289] [PMID: 29040564]
[2]
Bozorgmehr M, Gurung S, Darzi S, et al. Endometrial and menstrual blood mesenchymal stem/stromal cells: Biological properties and clinical application. Front Cell Dev Biol 2020; 8: 497.
[http://dx.doi.org/10.3389/fcell.2020.00497] [PMID: 32742977]
[3]
Jin S. Bipotent stem cells support the cyclical regeneration of endometrial epithelium of the murine uterus. Proc Natl Acad Sci USA 2019; 116(14): 6848-57.
[http://dx.doi.org/10.1073/pnas.1814597116] [PMID: 30872480]
[4]
Gargett CE, Chan RWS, Schwab KE. Endometrial stem cells. Curr Opin Obstet Gynecol 2007; 19(4): 377-83.
[http://dx.doi.org/10.1097/GCO.0b013e328235a5c6] [PMID: 17625422]
[5]
Gargett CE, Masuda H. Adult stem cells in the endometrium. Mol Hum Reprod 2010; 16(11): 818-34.
[http://dx.doi.org/10.1093/molehr/gaq061] [PMID: 20627991]
[6]
Lee J, Park H, Moon S, Do JT, Hong K, Choi Y. Expression and regulation of CD73 during the estrous cycle in mouse uterus. Int J Mol Sci 2021; 22(17): 9403.
[http://dx.doi.org/10.3390/ijms22179403] [PMID: 34502315]
[7]
Cousins FL, Pandoy R, Jin S, Gargett CE. The elusive endometrial epithelial stem/progenitor cells. Front Cell Dev Biol 2021; 9: 640319.
[http://dx.doi.org/10.3389/fcell.2021.640319] [PMID: 33898428]
[8]
Zhu X, Péault B, Yan G, Sun H, Hu Y, Ding L. Stem cells and endometrial regeneration: From basic research to clinical trial. Curr Stem Cell Res Ther 2019; 14(4): 293-304.
[http://dx.doi.org/10.2174/1574888X14666181205120110] [PMID: 30516114]
[9]
Kirkwood PM, Gibson DA, Smith JR, et al. Single‐cell RNA sequencing redefines the mesenchymal cell landscape of mouse endometrium. FASEB J 2021; 35(4): e21285.
[http://dx.doi.org/10.1096/fj.202002123R] [PMID: 33710643]
[10]
Hou X, Liu Y, Streuli I, et al. Endometrial regeneration in Asherman’s Syndrome: Clinical and translational evidence of stem cell therapies. Curr Stem Cell Res Ther 2019; 14(6): 454-9.
[http://dx.doi.org/10.2174/1574888X14666190213100528] [PMID: 30760192]
[11]
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.
[http://dx.doi.org/10.1186/s13287-021-02526-z] [PMID: 34425902]
[12]
Liu Y, Liang S, Yang F, et al. Biological characteristics of endometriotic mesenchymal stem cells isolated from ectopic lesions of patients with endometriosis. Stem Cell Res Ther 2020; 11(1): 346.
[http://dx.doi.org/10.1186/s13287-020-01856-8] [PMID: 32771033]
[13]
Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 3(2): 93-110.
[14]
Dera-Szymanowska A, Chmaj-Wierzchowska K, Horst N, et al. Immunomodulation inhibits the development of endometriosis in rats. J Physiol Pharmacol 2020; 71(1): 145-53.
[http://dx.doi.org/10.26402/jpp.2020.1.14] [PMID: 32554849]
[15]
Hayashi S, Nakamura T, Motooka Y, et al. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice. Redox Biol 2020; 37: 101726.
[http://dx.doi.org/10.1016/j.redox.2020.101726] [PMID: 32961443]
[16]
Chan RWS, Ng EHY, Yeung WSB. Identification of cells with colony-forming activity, self-renewal capacity, and multipotency in ovarian endometriosis. Am J Pathol 2011; 178(6): 2832-44.
[http://dx.doi.org/10.1016/j.ajpath.2011.02.025] [PMID: 21641404]
[17]
Zhai J, Vannuccini S, Petraglia F, Giudice LC. Adenomyosis: Mechanisms and pathogenesis. Semin Reprod Med 38(2-03): 129-43.
[http://dx.doi.org/10.1055/s-0040-1716687]
[18]
Bulun S, Cheng YH, Pavone M, et al. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med 2010; 28(1): 036-43.
[http://dx.doi.org/10.1055/s-0029-1242991] [PMID: 20104427]
[19]
Králíčková M, Vetvicka V, Fiala L, Laganà AS, Garzon S. The search for biomarkers in endometriosis: A long and windy road. Reprod Sci 2022; 29(6): 1667-73.
[http://dx.doi.org/10.1007/s43032-021-00668-2] [PMID: 34159571]
[20]
Lalami I, Abo C, Borghese B, Chapron C, Vaiman D. Genomics of Endometriosis: From genome wide association studies to exome sequencing. Int J Mol Sci 2021; 22(14): 7297.
[http://dx.doi.org/10.3390/ijms22147297] [PMID: 34298916]
[21]
Zhang Z, Ruan L, Lu M, Yao X. Analysis of key candidate genes and pathways of endometriosis pathophysiology by a genomics-bioinformatics approach. Gynecol Endocrinol 2019; 35(7): 576-81.
[http://dx.doi.org/10.1080/09513590.2019.1576609] [PMID: 30798642]
[22]
Hansen KA, Eyster KM. Genetics and genomics of endometriosis. Clin Obstet Gynecol 2010; 53(2): 403-12.
[http://dx.doi.org/10.1097/GRF.0b013e3181db7ca1] [PMID: 20436317]
[23]
Ferrero S. Proteomics in the diagnosis of endometriosis: Opportunities and challenges. Proteomics Clin Appl 2019; 13(3): 1800183.
[http://dx.doi.org/10.1002/prca.201800183] [PMID: 30556654]
[24]
Kobayashi Y, Fukutomi T, Mita S, Watanabe M, Suzuki A. Identification of biomarkers for drug-resistant endometriosis using clinical proteomics. Hum Cell 2021; 34(2): 394-9.
[http://dx.doi.org/10.1007/s13577-020-00465-0] [PMID: 33387360]
[25]
Hwang JH, Oh JJ, Wang T, et al. Identification of biomarkers for endometriosis in eutopic endometrial cells from patients with endometriosis using a proteomics approach. Mol Med Rep 2013; 8(1): 183-8.
[http://dx.doi.org/10.3892/mmr.2013.1469] [PMID: 23670619]
[26]
Holdsworth-Carson SJ, Churchill M, Donoghue JF, et al. Elucidating the role of long intergenic non-coding RNA 339 in human endometrium and endometriosis. Mol Hum Reprod 2021; 27(3): gaab010.
[http://dx.doi.org/10.1093/molehr/gaab010] [PMID: 33576410]
[27]
Bi J, Wang D, Cui L, Yang Q. RNA sequencing‐based long non‐coding RNA analysis and immunoassay in ovarian endometriosis. Am J Reprod Immunol 2021; 85(3): e13359.
[http://dx.doi.org/10.1111/aji.13359] [PMID: 33063885]
[28]
Laganà AS, Salmeri FM, Vitale SG, Triolo O, Götte M. Stem cell trafficking during endometriosis: May epigenetics play a pivotal role? Reprod Sci 2018; 25(7): 978-9.
[http://dx.doi.org/10.1177/1933719116687661] [PMID: 28100109]
[29]
Wu MH, Hsiao KY, Tsai SJ. Hypoxia: The force of endometriosis. J Obstet Gynaecol Res 2019; 45(3): 532-41.
[http://dx.doi.org/10.1111/jog.13900] [PMID: 30618168]
[30]
Li WN, Wu MH, Tsai SJ. Hypoxia and reproductive health: The role of hypoxia in the development and progression of endometriosis. Reproduction 2021; 161(1): F19-31.
[http://dx.doi.org/10.1530/REP-20-0267] [PMID: 33112784]
[31]
Horne AW, Ahmad SF, Carter R, et al. Repurposing dichloroacetate for the treatment of women with endometriosis. Proc Natl Acad Sci USA 2019; 116(51): 25389-91.
[http://dx.doi.org/10.1073/pnas.1916144116] [PMID: 31792175]
[32]
McKinnon B, Bertschi D, Wotzkow C, Bersinger NA, Evers J, Mueller MD. Glucose transporter expression in eutopic endometrial tissue and ectopic endometriotic lesions. J Mol Endocrinol 2014; 52(2): 169-79.
[http://dx.doi.org/10.1530/JME-13-0194] [PMID: 24412827]
[33]
Yang X, Devianti M, Yang YH, et al. Endometrial mesenchymal stem/stromal cell modulation of T cell proliferation. Reproduction 2018; 157(1): 43-52.
[http://dx.doi.org/10.1530/REP-18-0266] [PMID: 30392200]
[34]
Aleahmad M, Bozorgmehr M, Nikoo S, et al. Endometrial mesenchymal stem/stromal cells: The Enigma to code messages for generation of functionally active regulatory T cells. Stem Cell Res Ther 2021; 12(1): 536.
[http://dx.doi.org/10.1186/s13287-021-02603-3] [PMID: 34627370]
[35]
Chen P, Mamillapalli R, Habata S, Taylor HS. Endometriosis stromal cells induce bone marrow mesenchymal stem cell differentiation and PD-1 expression through paracrine signaling. Mol Cell Biochem 2021; 476(4): 1717-27.
[http://dx.doi.org/10.1007/s11010-020-04012-1] [PMID: 33428059]
[36]
Laganà AS, Salmeri FM, Ban Frangež H, Ghezzi F, Vrtačnik-Bokal E, Granese R. Evaluation of M1 and M2 macrophages in ovarian endometriomas from women affected by endometriosis at different stages of the disease. Gynecol Endocrinol 2020; 36(5): 441-4.
[http://dx.doi.org/10.1080/09513590.2019.1683821] [PMID: 31663401]
[37]
Zhang J, Rong Y, Luo C, Cui W. Bone marrow mesenchymal stem cell-derived exosomes prevent osteoarthritis by regulating synovial macrophage polarization. Aging 2020; 12(24): 25138-52.
[http://dx.doi.org/10.18632/aging.104110] [PMID: 33350983]
[38]
Yu X, Ren H, Liu T, Yong M, Zhong H. Expression and significance of ERβ and TrkB in endometriosis. Clin Exp Obstet Gynecol 2016; 43(1): 75-81.
[http://dx.doi.org/10.12891/ceog2027.2016] [PMID: 27048022]
[39]
Xue W, Yao X, Ting G, et al. BPA modulates the WDR5/TET2 complex to regulate ERbeta expression in eutopic endometrium and drives the development of endometriosis. Environ Pollut 268(Pt B): 115748.
[http://dx.doi.org/10.1016/j.envpol.2020.115748]
[40]
Gou Y, Li X, Li P, et al. Estrogen receptor β upregulates CCL2 via NF-κB signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis. Hum Reprod 2019; 34(4): 646-58.
[http://dx.doi.org/10.1093/humrep/dez019] [PMID: 30838396]
[41]
Králíčková M, Laganà AS, Ghezzi F, Vetvicka V. Endometriosis and risk of ovarian cancer: What do we know? Arch Gynecol Obstet 2020; 301(1): 1-10.
[http://dx.doi.org/10.1007/s00404-019-05358-8] [PMID: 31745637]
[42]
Pejovic T, Thisted S, White M, Nezhat FR. Endometriosis and endometriosis-associated ovarian cancer (EAOC). Adv Exp Med Biol 2020; 1242: 73-87.
[http://dx.doi.org/10.1007/978-3-030-38474-6_5] [PMID: 32406029]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy