Skip to main content

Advertisement

SpringerLink
Log in

Stem Cell Markers Describe a Transition From Somatic to Pluripotent Cell States in a Rat Model of Endometriosis

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Objective

To study Thy1 as a fibroblast marker, SSEA1 as a marker of intermediate pluripotency, and Oct4 as a marker of established pluripotency in rat model of endometriosis.

Design

In vivo animal study.

Materials and Methods

Endometriosis was induced in 20 albino female rats through autologous transplantation of one uterine horn to mesentery of intestine. Other 20 rats had their horn removed without transplantation (controls). Rats were sacrificed 4 weeks after induction surgery. Ectopic, eutopic, and control endometria were harvested from endometriosis and control animals respectively. Quantitative syber green based RT-PCR was used to detect expression of Thy-1 (CD90), FUT4 (SSEA1), and POU5F1 (Oct4) genes in tissues. Relative expression was normalized to that of b actin. Thy1, SSEA1, and Oct4 protein expression were detected by immunohistochemistry.

Results

Ectopic endometrium expressed significantly higher mRNA of Oct4 and SSEA1 as compared to control endometrium. Expression levels of Oct4 and SSEA1 were comparable between ectopic and eutopic endometria and between eutopic and control endometria. Thy1 (CD90) gene expression level was comparable among ectopic, eutopic, and control endometria. Oct4 immunoscore were significantly higher in ectopic (6.6±0.91) than eutopic (2.5±0.78) or control endometrium (3.7±0.1) (P value 0.02). Thy1 and SSEA1 immunoscores were comparable among all three types of endometria.

Conclusions

Using rat model of endometriosis, ectopic endometrium showed significantly higher Oct4, and SSEA1, but similar Thy1 gene expression to that of control endometrium. This indicates increased transition from somatic to pluripotent cell states in ectopic endometrium which may play a role in endometriosis pathogenesis.

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.

Institutional subscriptions

Similar content being viewed by others

References

  1. Schleedoorn MJ, Nelen WL, Dunselman GA, Vermeulen N, Endokey Group. Endokey Group. Selection of key recommendations for the management of women with endometriosis by an international panel of patients and professionals. Hum Reprod. 2016;31(6):1208–18.

    Article  CAS  PubMed  Google Scholar 

  2. Othman ER, Hornung D, Hussein M, et al. Soluble tumor necrosis alpha receptors in the serum of endometriosis patients. Eur J Obstet Gynecol Reprod Biol. 2016;200:1–5.

    Article  CAS  PubMed  Google Scholar 

  3. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24(2):235–258.

    Article  CAS  PubMed  Google Scholar 

  4. Kappou D, Matalliotakis M, Matalliotakis I. Medical treatments for endometriosis. Minerva Ginecol. 2010;62(5):415–432.

    CAS  PubMed  Google Scholar 

  5. Falcone T, Lebovic D. Clinical management of endometriosis. Obstet Gynecol. 2011;118(3):691–705.

    Article  CAS  PubMed  Google Scholar 

  6. Giudice L. Clinical practice: endometriosis. N Engl J Med. 2010; 362(25):2389–2398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dunselman GA, Vermeulen N, Becker C, et al; European Society of Human Reproduction and Embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014; 29(3):400–412.

    Article  CAS  PubMed  Google Scholar 

  8. Shakiba K, Bena J, McGill K, Minge J, Falcone T. Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery. Obstet Gynecol. 2008;111(6):1285–1292.

    Article  PubMed  Google Scholar 

  9. Nnoaham KE, Hummelshoj L, Webster P, et al; World Endometriosis Research Foundation Global Study of Women’s Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366–373.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Giudice L, Kao L. Endometriosis. Lancet. 2004;364(9447):1789–1799.

    Article  PubMed  Google Scholar 

  11. Rogers PA, D’Hooghe TM, Fazleabas A, et al. Defining future directions for endometriosis research: workshop report from the 2011 World Congress of Endometriosis in Montpellier, France. Reprod Sci. 2013;20(5):483–499.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–519.

    Article  CAS  PubMed  Google Scholar 

  13. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14(4):422–469.

    Article  Google Scholar 

  14. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279.

    Article  CAS  PubMed  Google Scholar 

  15. Du H, Taylor HS. Stem cells and female reproduction. Reprod Sci. 2009;16(2):126–139.

    Article  PubMed  Google Scholar 

  16. Chan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod. 2004; 70(6):1738–1750.

    Article  CAS  PubMed  Google Scholar 

  17. Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod. 2009;80(6):1136–1145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mints M, Jansson M, Sadeghi B, et al. Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient. Hum Reprod. 2008;23(1):139.

    Article  CAS  PubMed  Google Scholar 

  19. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1): 81–85.

    Article  CAS  PubMed  Google Scholar 

  20. Ikoma T, Kyo S, Maida Y, et al. Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. Am J Obstet Gynecol. 2009;201(6):608.e1–608.e8.

    Article  CAS  Google Scholar 

  21. Wolff EF, Wolff AB, Hongling Du, Taylor HS. Demonstration of multipotent stem cells in the adult human endometrium by in vitro chondrogenesis. Reprod Sci. 2007;14(6):524–533.

    Article  CAS  PubMed  Google Scholar 

  22. Dimitrov R, Timeva T, Kyurkchiev D, et al. Characterization of clonogenic stromal cells isolated from human endometrium. Reproduction. 2008;135(4):551–558.

    Article  CAS  PubMed  Google Scholar 

  23. Gargett CE, Schwab KE, Brosens JJ, Puttemans P, Benagiano G, Brosens I. Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. Mol Hum Reprod. 2014;20(7):591–598.

    Article  CAS  PubMed  Google Scholar 

  24. Figueira PG, Abra˜o MS, Krikun G, Taylor HS. Stem cells in endometrium and their role in the pathogenesis of endometriosis. Ann N Y Acad Sci. 2011;1221:10–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hufnagel D, Li F, Cosar E, Krikun G, Taylor HS. Role of stem cells in the etiology and pathophysiology of endometriosis. Semin Reprod Med. 2015;33(5):333–340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chan RW, Ng EH, Yeung WS. Identification of cells with colony forming activity, self-renewal capacity, and multipotency in ovarian endometriosis. Am J Pathol. 2011;178(6):2832–2844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Djokovic D, Calhaz-Jorge C. Somatic stem cells and their dysfunction in endometriosis. Front Surg. 2014;1:51.

    PubMed  Google Scholar 

  28. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007; 25(8):2082–2086.

    Article  CAS  PubMed  Google Scholar 

  29. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–676.

    Article  CAS  PubMed  Google Scholar 

  30. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318(5858):1917–1920.

    Article  CAS  PubMed  Google Scholar 

  31. Daley G. Common themes of dedifferentiation in somatic cell reprogramming and cancer. Cold Spring Harb Symp Quant Biol. 2008;73:171–174.

    Article  CAS  PubMed  Google Scholar 

  32. Friedmann-Morvinski D, Verma IM. Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep. 2014;15(3):244–235.

    Google Scholar 

  33. Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002;1(3):269–277.

    Article  CAS  PubMed  Google Scholar 

  34. Friedmann-Morvinski D, Bushong EA, Ke E, et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science. 2012;338(6110):1080–1084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Soda Y, Marumoto T, Friedmann-Morvinski D, et al. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci U S A. 2011;108(11):4274–4280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schwitalla S, Fingerle AA, Cammareri P, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem celllike properties. Cell. 2013;152(1-2):25–38.

    Article  CAS  PubMed  Google Scholar 

  37. Chaffer CL, Marjanovic ND, Lee T, et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013;154(1):61–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gidekel Friedlander SY, Chu GC, Snyder EL, et al. Contextdependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell. 2009;16(5):379–389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Kumar SM, Liu S, Lu H, et al. Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene. 2012; 31(47):4898–4911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pelch KE, Schroder AL, Kimball PA, Sharpe-Timms KL, Davis JW, Nagel SC. Aberrant gene expression profile in mouse model of endometriosis mirrors that observed in women. Fertil Steril. 2010;93(5):1615–1162.

    Google Scholar 

  41. Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985;44(5):684–694.

    Article  CAS  PubMed  Google Scholar 

  42. Sharpe-Timms KL. Using rats as a research model for the study of endometriosis. Ann N Y Acad Sci. 2002;955:318–327. discussion 340-342, 396-406.

    Article  PubMed  Google Scholar 

  43. Gotte M, Wolf M, Staebler A, et al. Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma. J Pathol. 2008;215(3):317–329.

    Article  CAS  PubMed  Google Scholar 

  44. Forte A, Schettino MT, Finicelli M, et al. Expression pattern of stemness-related genes in human endometrial and endometriotic tissues. Mol Med. 2009;15(11-12:392–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Song Y, Xiao L, Fu J, et al. Increased expression of the pluripotency markers sex-determining region Y-box 2 and Nanog homeobox in ovarian endometriosis. Reprod Biol Endocrinol. 2014;12:42.

  46. Kao AP, Wang KH, Chang CC, et al. Comparative study of human eutopic and ectopic endometrial mesenchymal stem cells and the development of an in vivo endometriotic invasion model. Fertil Steril. 2011;95(4):1308–1315.e1.

    Article  CAS  PubMed  Google Scholar 

  47. Moggio A, Pittatore G, Cassoni P, Marchino GL, Revelli A, Bussolati B. Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98(6): 1521–1530.e1522.

    Article  CAS  PubMed  Google Scholar 

  48. Nyholt DR, Low SK, Anderson CA, et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet. 2012;44(12):1355–1359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod. 2002;17(10):2725–2736.

    Article  CAS  PubMed  Google Scholar 

  50. Gargett CE, Masuda H. Adult stem cells in the endometrium. Mol Hum Reprod. 2010;16(11):818–834.

    Article  CAS  PubMed  Google Scholar 

  51. Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008;1127:106–115.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Valentijn AJ, Palial K, Al-Lamee H, et al. SSEA-1 isolates human endometrial basal glandular epithelial cells: phenotypic and functional characterization and implications in the pathogenesis of endometriosis. Hum Reprod. 2013;28(10):2695–2708.

    Article  CAS  PubMed  Google Scholar 

  53. Gargett CE, Schwab KE, Deane JA. Endometrial stem/progenitor cells: the first 10 years. Hum Reprod Update. 2016;22(2):137–163.

    CAS  PubMed  Google Scholar 

  54. Bratincsá kA, Brownstein MJ, Cassiani-Ingoni R, et al. CD45- positive blood cells give rise to uterine epithelial cells in mice. Stem Cells. 2007;25(11):2820–2826.

    Article  CAS  Google Scholar 

  55. Morelli SS, Rameshwar P, Goldsmith LT. Experimental evidence for bone marrow as a source of non-hematopoietic endometrial stromal and epithelial compartment cells in a murine model. Biol Reprod. 2013;89(1):7.

    Article  PubMed  CAS  Google Scholar 

  56. Becker CM, Beaudry P, Funakoshi T, et al. Circulating endothelial progenitor cells are up-regulated in a mouse model of endometriosis. Am J Pathol. 2011;178(4):1782–1791.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kulak J Jr, Fischer C, Komm B, Taylor HS. Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model. Endocrinology. 2011;152(8):3226–3232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sakr S, Naqvi H, Komm B, Taylor HS. 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. 2014; 155(4):1489–1497.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Wang X, Mamillapalli R, Mutlu L, Du H, Taylor HS. Chemoattraction of bone marrow-derived stem cells towards human endometrial stromal cells is mediated by estradiol regulated CXCL12 and CXCR4 expression. Stem Cell Res (Amst). 2015;15(1):14–22.

    Article  CAS  Google Scholar 

  60. Ruiz A, Salvo VA, Ruiz LA, Báez P, García M, Flores I. Basal and steroid hormone-regulated expression of CXCR4 in human endometrium and endometriosis. Reprod Sci. 2010;17(10): 894–903.

    Article  CAS  PubMed  Google Scholar 

  61. Cervelló I, Gil-Sanchis C, Mas A, et al. Bone marrow-derived cells from male donors do not contribute to the endometrial side population of the recipient. PLoS One. 2012;7(1): e30260.

    Google Scholar 

  62. Kotton DN, Fabian AJ, Mulligan RC. Failure of bone marrow to reconstitute lung epithelium. Am J Respir Cell Mol Biol. 2005; 33(4):328–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Duffield JS, Bonventre JV. Kidney tubular epithelium is restored without replacement with bone marrow-derived cells during repair after ischemic injury. Kidney Int. 2005;68(5):1956–1961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Du H, Naqvi H, Taylor HS. Ischemia/reperfusion injury promotes and granulocyte colony stimulating factor inhibits migration of bone marrow-derived stem cells to endometrium. Stem Cells Dev. 2012;21(18):3324–3331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Alawadhi F, Du H, Cakmak H, Taylor HS. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman’s syndrome. PLoS One. 2014;9(5): e96662.

    Google Scholar 

  66. Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic non stem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A. 2011;108(19):7950–7955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Roy S, Gascard P, Dumont N, et al. Rare somatic cells from human breast tissue exhibit extensive lineage plasticity. Proc Natl Acad Sci U S A. 2013;110(12):4598–4603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tata PR, Mou H, Pardo-Saganta A, et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature. 2013; 503(7475):218–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Van Es JH, Sato T, van de Wetering M, et al. Dll1 þ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol. 2012;14(10):1099–1104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Vermeulen L, De Sousa EMF, van der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12(5):468–476.

    Article  CAS  PubMed  Google Scholar 

  71. Polo JM, Anderssen E, Walsh RM, et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell. 2012;151(7): 1617–1632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chang JH, Au HK, Lee WC, et al. Expression of the pluripotent transcription factor OCT4 promotes cell migration in endometriosis. Fertil Steril. 2013;99(5):1332–1339.

    Article  CAS  PubMed  Google Scholar 

  73. Gotte M, Wolf M, Staebler A, Buchweitz O, Kiesel L, Schuring AN. Aberrant expression of the pluripotency marker SOX-2 in endometriosis. Fertil Steril. 2011;95(1):338–341.

    Article  PubMed  CAS  Google Scholar 

  74. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010–1012.

    Article  CAS  PubMed  Google Scholar 

  75. Grechukhina O, Petracco R, Popkhadze S, et al. A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med. 2012;4(3):206–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. González-Ramos R, Defrère S, Devoto L. Nuclear factor-kappa B: a main regulator of inflammation and cell survival in endometriosis pathophysiology. Fertil Steril. 2012;98(3):520–528.

    Article  PubMed  CAS  Google Scholar 

  77. Kaponis A, Iwabe T, Taniguchi F, et al. The role of NF-kappa B in endometriosis. Front Biosci (Schol Ed). 2012;4:1213–1234.

    Google Scholar 

  78. Matsuzaki S, Darcha C. In vitro effects of a small-molecule antagonist of the Tcf/ß-catenin complex on endometrial and endometriotic cells of patients with endometriosis. PLoS One. 2013; 8(4): e61690.

    Google Scholar 

  79. Matsuzaki S, Darcha C. Involvement of the Wnt/ß-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis. PLoS One. 2013;8(10): e76808.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. OB-GYN Department, Assiut University, Egypt

    Essam Rashad Othman MD

  2. Center of Excellence of Stem Cells and Regenerative Medicine (CESCRM), Assiut University, Egypt

    Essam Rashad Othman MD

  3. Histology Department, Assiut University, Egypt

    Fatma Yassine Meligy PhD

  4. Medical Biochemistry Department, Assiut University, Egypt

    Ayat Abdel-Rahman Sayed PhD

  5. Medical Microbiology and Immunology, Assiut University, Egypt

    Mohamed Ahmed El-Mokhtar PhD

  6. Pathology Department, Assiut University, Egypt

    Abeer Mohamed Refaiy PhD

Authors
  1. Essam Rashad Othman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatma Yassine Meligy PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayat Abdel-Rahman Sayed PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohamed Ahmed El-Mokhtar PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abeer Mohamed Refaiy PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Essam Rashad Othman MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Othman, E.R., Meligy, F.Y., Sayed, A.AR. et al. Stem Cell Markers Describe a Transition From Somatic to Pluripotent Cell States in a Rat Model of Endometriosis. Reprod. Sci. 25, 873–881 (2018). https://doi.org/10.1177/1933719117697124

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719117697124

Keywords

Search

Navigation