Skip to main content

Advertisement

SpringerLink
Log in

TGF-β1 in Seminal Plasma Promotes Endometrial Mesenchymal Stem Cell Growth via p42/44 and Akt Pathway in Patients With or Without Endometriosis

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

Abstract

The cause of endometriosis, which is characterized by the existence of functional endometrial tissue outside the uterine cavity, is poorly understood. Seminal plasma (SP) is rich in multiple cytokines that may promote endometrial tissue survival. Here, we evaluated the effect of SP on growth of endometrial mesenchymal stem cells (MSCs) from women with endometriosis (E-MSCs) and women without endometriosis (NE-MSCs). Proliferation, cell foci formation, cell cycle progression, and growth marker expression of E- and NE-MSCs were promoted by SP. These effects may be mediated through activation of transforming growth factor beta 1 (TGF-β1), Akt, and p42/44 signaling, which enhances CDK2 and CDK6 expression and accelerates cell cycle progression. Xenografts exposed to SP exhibited a three-fold increase in volume and four-fold increase in weight after 14 days. Our findings demonstrate that TGF-β1 in SP may promote endometrial tissue survival which will allow us to understand the pathogenesis and develop novel approaches for prevention and therapies of endometriosis.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–99.

    Article  Google Scholar 

  2. D'Hooghe TM, Debrock S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum Reprod Update. 2002;8(1):84–8.

    Article  Google Scholar 

  3. Cervello I, Mas A, Gil-Sanchis C, et al. Reconstruction of endometrium from human endometrial side population cell lines. Plos One. 2011;6(6):e21221.

    Article  CAS  Google Scholar 

  4. Moggio A, Pittatore G, Cassoni P, et al. Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98(6):1521-30.e2.

    Article  Google Scholar 

  5. Klemmt L, Scialli AR. The transport of chemicals in semen. Birth Defects Res B Dev Reprod Toxicol. 2005;74(2):119–31.

    Article  CAS  Google Scholar 

  6. Ibrahim MG, Elghonaimy EA, Schafer S, et al. Seminal plasma (SP) induces a rapid transforming growth factor beta 1 (TGFbeta1)-independent up-regulation of epithelial-mesenchymal transdifferentiation (EMT) and myofibroblastic metaplasia-markers in endometriotic (EM) and endometrial cells. Arch Gynecol Obstet. 2019;299(1):173–83.

    Article  CAS  Google Scholar 

  7. Khan KN, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, et al. Effect of human seminal fluid on the growth of endometrial cells of women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2010;149(2):204–9.

    Article  CAS  Google Scholar 

  8. McGuane JT, Watson KM, Zhang J, et al. seminal plasma promotes lesion development in a xenograft model of endometriosis. Am J Pathol. 2015;185(5):1409–22.

    Article  CAS  Google Scholar 

  9. Chen JC, Johnson BA, Erikson DW, Piltonen TT, Barragan F, Chu S, et al. Seminal plasma induces global transcriptomic changes associated with cell migration, proliferation and viability in endometrial epithelial cells and stromal fibroblasts. Hum Reprod. 2014;29(6):1255–70.

    Article  CAS  Google Scholar 

  10. Hull ML, Johan MZ, Hodge WL, Robertson SA, Ingman WV. Host-derived TGFB1 deficiency suppresses lesion development in a mouse model of endometriosis. Am J Pathol. 2012;180(3):880–7.

    Article  CAS  Google Scholar 

  11. Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer. J Clin Oncol. 2005;23(9):2078–93.

    Article  CAS  Google Scholar 

  12. Zhang J, Li H, Yi D, Lai C, Wang H, Zou W, et al. Knockdown of vascular cell adhesion molecule 1 impedes transforming growth factor beta 1-mediated proliferation, migration, and invasion of endometriotic cyst stromal cells. Reprod Biol Endocrinol. 2019;17(1):69.

    Article  Google Scholar 

  13. Young VJ, Brown JK, Saunders PT, et al. The peritoneum is both a source and target of TGF-beta in women with endometriosis. Plos One. 2014;9(9):e106773.

    Article  Google Scholar 

  14. Honda H, Barrueto FF, Gogusev J, Im DD, Morin PJ. Serial analysis of gene expression reveals differential expression between endometriosis and normal endometrium. Possible roles for AXL and SHC1 in the pathogenesis of endometriosis. Reprod Biol Endocrinol. 2008;6:59.

    Article  Google Scholar 

  15. Li B, Qiu T, Zhang P, Wang X, Yin Y, Li S. IKVAV regulates ERK1/2 and Akt signalling pathways in BMMSC population growth and proliferation. Cell Prolif. 2014;47(2):133–45.

    Article  CAS  Google Scholar 

  16. Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell. 1997;88(4):435–7.

    Article  CAS  Google Scholar 

  17. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. 2010.

    Google Scholar 

  18. Li J, Dai Y, Zhu H, Jiang Y, Zhang S. Endometriotic mesenchymal stem cells significantly promote fibrogenesis in ovarian endometrioma through the Wnt/beta-catenin pathway by paracrine production of TGF-beta1 and Wnt1. Hum Reprod. 2016;31(6):1224–35.

    Article  CAS  Google Scholar 

  19. Liu H, Kemeny DM, Heng BC, Ouyang HW, Melendez AJ, Cao T. The immunogenicity and immunomodulatory function of osteogenic cells differentiated from mesenchymal stem cells. J Immunol. 2006;176(5):2864–71.

    Article  CAS  Google Scholar 

  20. Matsuzaki S, Darcha C. Antifibrotic properties of epigallocatechin-3-gallate in endometriosis. Hum Reprod. 2014;29(8):1677–87.

    Article  CAS  Google Scholar 

  21. Shinozaki M, Kawara S, Hayashi N, Kakinuma T, Igarashi A, Takehara K. Induction of subcutaneous tissue fibrosis in newborn mice by transforming growth factor beta--simultaneous application with basic fibroblast growth factor causes persistent fibrosis. Biochem Biophys Res Commun. 1997;240(2):292–7.

    Article  CAS  Google Scholar 

  22. 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):1136–45.

    Article  CAS  Google Scholar 

  23. Jozwiakowski SK, Kummer S, Gari K. Human DNA polymerase delta requires an iron-sulfur cluster for high-fidelity DNA synthesis. Life Sci Alliance. 2019;2(4).

  24. Miloso M, Scuteri A, Foudah D, Tredici G. MAPKs as mediators of cell fate determination: an approach to neurodegenerative diseases. Curr Med Chem. 2008;15(6):538–48.

    Article  CAS  Google Scholar 

  25. Dai Y, Li F, Wu L, Wang R, Li P, Yan S, et al. Roxithromycin treatment inhibits TGF-beta1-induced activation of ERK and AKT and down-regulation of caveolin-1 in rat airway smooth muscle cells. Respir Res. 2014;15:96.

    Article  Google Scholar 

  26. Cheffer A, Tarnok A, Ulrich H. Cell cycle regulation during neurogenesis in the embryonic and adult brain. Stem Cell Rev Rep. 2013;9(6):794–805.

    Article  CAS  Google Scholar 

  27. Soomro J, Lu Z, Gui H, Zhang B, Shen Z. Synchronous and time-dependent expression of cyclins, cyclin-dependent kinases, and apoptotic genes in the rumen epithelia of butyrate-infused goats. Front Physiol. 2018;9:496.

    Article  Google Scholar 

  28. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182(3):311–22.

    Article  CAS  Google Scholar 

  29. Nikoo S, Ebtekar M, Jeddi-Tehrani M, Shervin A, Bozorgmehr M, Vafaei S, et al. Menstrual blood-derived stromal stem cells from women with and without endometriosis reveal different phenotypic and functional characteristics. Mol Hum Reprod. 2014;20(9):905–18.

    Article  CAS  Google Scholar 

  30. Pittatore G, Moggio A, Benedetto C, Bussolati B, Revelli A. Endometrial adult/progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy. Reprod Sci. 2014;21(3):296–304.

    Article  CAS  Google Scholar 

  31. Robertson SA, Robertson SA. Seminal plasma and male factor signalling in the female reproductive tract. Cell Tissue Res. 2005;322(1):43–52.

    Article  Google Scholar 

  32. Schmitz KJ, Wohlschlaeger J, Lang H, Sotiropoulos GC, Malago M, Steveling K, et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol. 2008;48(1):83–90.

    Article  CAS  Google Scholar 

  33. Tian Y, Qi M, Hong Z, Li Y, Yuan Y, du Y, et al. Activation of transient receptor potential vanilloid 4 promotes the proliferation of stem cells in the adult hippocampal dentate gyrus. Mol Neurobiol. 2017;54(8):5768–79.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Funding

This research was supported by the Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ19H040014 and No. LY20C08002, the general project of medicine and health in Zhejiang Province of China No. 2018KY109 and 2018RC009, and National Key Research and Development Program of China No. 2018YFC1004800.

Author information

Authors and Affiliations

  1. Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China

    Jing Li, Yongdong Dai, Chao Li, Yanling Zhang, Haiyan Zhu, Xiaoying Jin, Xiang Lin, Jianmin Chen, Lijuan Zhao & Songying Zhang

Authors
  1. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongdong Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haiyan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoying Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiang Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jianmin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lijuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Songying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Songying Zhang.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

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

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Dai, Y., Li, C. et al. TGF-β1 in Seminal Plasma Promotes Endometrial Mesenchymal Stem Cell Growth via p42/44 and Akt Pathway in Patients With or Without Endometriosis. Reprod. Sci. 29, 723–733 (2022). https://doi.org/10.1007/s43032-021-00562-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-021-00562-x

Keywords

Search

Navigation