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CXCL12 Attracts Bone Marrow-Derived Cells to Uterine Leiomyomas

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Abstract

Uterine leiomyomas, also known as fibroids or myomas, are a common benign gynecologic tumor found in women of reproductive age. Though advances have been made in understanding leiomyomas, the etiology and pathogenesis of this disease are not fully characterized. Current evidence supports a role of putative human uterine stem/progenitor cells in the onset of uterine disease such as uterine myomas. In this study, we report that increased expression of CXCL12 in leiomyomas recruits bone marrow-derived cells (BMDCs) that may contribute to leiomyoma growth. Tissue was collected from leiomyomas or control myometrium from women with or without leiomyomas. qRT-PCR analysis showed increased expression of CXCL12 and decreased CXCR4 expression in the leiomyoma and myometrium of women with leiomyoma compared with normal myometrium. Increased CXCL12 protein secretion from cultured myoma cells was confirmed by ELISA. Further, we found that BMDCs migration was increased toward leiomyoma conditioned medium compared with conditioned medium from normal myometrium. CXCR4 antagonist AMD3100 completely blocked this migration. Engraftment of BMDCs significantly increased in myoma of mouse uteri treated with CXCL12 compared with placebo. We conclude that CXCL12 may play a role in leiomyomas growth by attracting bone marrow-derived cells to leiomyoma. Therefore, CXCL12 and its receptors are novel targets for leiomyoma therapy.

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References

  1. Wallach EE, Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol. 2004;104(2):393–406.

    Article  PubMed  Google Scholar 

  2. Bulun SE. Tissue stem cells and uterine physiology and pathology. Semin Reprod Med. 2015;33(5):313–4.

    Article  PubMed  Google Scholar 

  3. Taylor HS. Fibroids: when should they be removed to improve in vitro fertilization success. Fertil Steril. 2018;109(5):784–5.

    Article  PubMed  Google Scholar 

  4. Cao T, Jiang Y, Wang Z, Zhang N, al-Hendy A, Mamillapalli R, et al. H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas. Oncogene. 2019;38(27):5356–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cermik D, Arici A, Taylor HS. Coordinated regulation of HOX gene expression in myometrium and uterine leiomyoma. Fertil Steril. 2002;78(5):979–84.

    Article  PubMed  Google Scholar 

  6. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–34.

    Article  CAS  PubMed  Google Scholar 

  7. Sinclair DC, Mastroyannis A, Taylor HS. Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-beta3. J Clin Endocrinol Metab. 2011;96(2):412–21.

    Article  CAS  PubMed  Google Scholar 

  8. Marsh EE, Bulun SE. Steroid hormones and leiomyomas. Obstet Gynecol Clin N Am. 2006;33(1):59–67.

    Article  Google Scholar 

  9. Parker WH. Uterine myomas: management. Fertil Steril. 2007;88(2):255–71.

    Article  PubMed  Google Scholar 

  10. Bulun SE. Uterine fibroids. N Engl J Med. 2013;369(14):1344–55.

    Article  CAS  PubMed  Google Scholar 

  11. Doherty L, Mutlu L, Sinclair D, Taylor H. Uterine fibroids: clinical manifestations and contemporary management. Reprod Sci (Thousand Oaks, Calif). 2014;21(9):1067–92.

    Article  Google Scholar 

  12. Segars JH. Uterine fibroid research: a work in progress. Reprod Sci (Thousand Oaks, Calif.). 2014;21(9):1065–6.

    Article  Google Scholar 

  13. Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. 2003;111(8):1037–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sozen I, Arici A. Cellular biology of myomas: interaction of sex steroids with cytokines and growth factors. Obstet Gynecol Clin N Am. 2006;33(1):41–58.

    Article  Google Scholar 

  15. Blake RE. Leiomyomata uteri: hormonal and molecular determinants of growth. J Natl Med Assoc. 2007;99(10):1170–84.

    PubMed  PubMed Central  Google Scholar 

  16. Ciarmela P, Islam MS, Reis FM, Gray PC, Bloise E, Petraglia F, et al. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update. 2011;17(6):772–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ono M, Qiang W, Serna VA, Yin P, Coon JS 5th, Navarro A, et al. Role of stem cells in human uterine leiomyoma growth. PLoS One. 2012;7(5):e36935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Szotek PP, Chang HL, Zhang L, Preffer F, Dombkowski D, Donahoe PK, et al. Adult mouse myometrial label-retaining cells divide in response to gonadotropin stimulation. Stem Cells. 2007;25(5):1317–25.

    Article  CAS  PubMed  Google Scholar 

  19. Ono M, Maruyama T, Masuda H, Kajitani T, Nagashima T, Arase T, et al. Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proc Natl Acad Sci U S A. 2007;104(47):18700–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tal R, Shaikh S, Pallavi P, Tal A, López-Giráldez F, Lyu F, et al. Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy. PLoS Biol. 2019;17(9):e3000421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sahin Ersoy G, Zolbin MM, Cosar E, Moridi I, Mamillapalli R, Taylor HS. CXCL12 promotes stem cell recruitment and uterine repair after injury in Asherman’s syndrome. Mol Ther Methods Clin Dev. 2017;4:169–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Moridi I, Mamillapalli R, Cosar E, Ersoy GS, Taylor HS. Bone marrow stem cell chemotactic activity is induced by elevated CXCl12 in endometriosis. Reprod Sci (Thousand Oaks, Calif.). 2017;24(4):526–33.

    Article  CAS  Google Scholar 

  23. Barr A, Manning D. G Proteins Techniques of Analysis. Boca Raton: CRC Press, Inc.; 1999. p. 227–45.

    Google Scholar 

  24. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  25. Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80(1):79–85.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Drayer SM, Catherino WH. Prevalence, morbidity, and current medical management of uterine leiomyomas. Int J Gynaecol Obstet. 2015;131(2):117–22.

    Article  PubMed  Google Scholar 

  27. Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012;206(3):211.e211–9.

    Article  Google Scholar 

  28. Mas A, Nair S, Laknaur A, Simon C, Diamond MP, Al-Hendy A. Stro-1/CD44 as putative human myometrial and fibroid stem cell markers. Fertil Steril. 2015;104(1):225–234.e223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yin P, Ono M, Moravek MB, Coon JS 5th, Navarro A, Monsivais D, et al. Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo. J Clin Endocrinol Metab. 2015;100(4):E601–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mas A, Stone L, O'Connor PM, Yang Q, Kleven D, Simon C, et al. Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. Stem Cells. 2017;35(3):666–78.

    Article  CAS  PubMed  Google Scholar 

  31. Prusinski Fernung LE, Yang Q, Sakamuro D, Kumari A, Mas A, Al-Hendy A. Endocrine disruptor exposure during development increases incidence of uterine fibroids by altering DNA repair in myometrial stem cells. Biol Reprod. 2018;99(4):735–48.

    PubMed  PubMed Central  Google Scholar 

  32. Liu S, Yin P, Kujawa SA, Coon JS, Okeigwe I, Bulun SE. Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma. Oncogene. 2019;38(15):2722–35.

    Article  CAS  PubMed  Google Scholar 

  33. 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. 2015;15(1):14–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lian WS, Ko JY, Chen YS, Ke HJ, Hsieh CK, Kuo CW, et al. MicroRNA-29a represses osteoclast formation and protects against osteoporosis by regulating PCAF-mediated RANKL and CXCL12. Cell Death Dis. 2019;10(10):705.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. Jama. 2004;292(1):81–5.

    Article  CAS  PubMed  Google Scholar 

  36. Simoni M, Taylor HS. Therapeutic strategies involving uterine stem cells in reproductive medicine. Curr Opin Obstet Gynecol. 2018;30(3):209–16.

    Article  PubMed  Google Scholar 

  37. Liu Y, Tal R, Pluchino N, Mamillapalli R, Taylor HS. Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J Cell Mol Med. 2018;22(1):67–76.

    Article  PubMed  Google Scholar 

  38. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8):2082–6.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by NIH U54 HD052668 and R01 HD076422.

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA

    Irene Moridi, Ramanaiah Mamillapalli, Pinar H. Kodaman, Shutaro Habata, Tran Dang & Hugh S. Taylor

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  1. Irene Moridi
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  2. Ramanaiah Mamillapalli
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  3. Pinar H. Kodaman
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  4. Shutaro Habata
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  5. Tran Dang
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  6. Hugh S. Taylor
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Correspondence to Ramanaiah Mamillapalli.

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Moridi, I., Mamillapalli, R., Kodaman, P.H. et al. CXCL12 Attracts Bone Marrow-Derived Cells to Uterine Leiomyomas. Reprod. Sci. 27, 1724–1730 (2020). https://doi.org/10.1007/s43032-020-00166-x

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  • DOI: https://doi.org/10.1007/s43032-020-00166-x

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