Comparison of the regenerative effects of bone marrow/adipose-derived stem cells in the Asherman model following local or systemic administration

Abstract

Purpose

Cell therapy is a promising strategy for the treatment of Asherman’s syndrome (AS), but the origin of these cells and injection route influence the therapeutic effect and complications of cell therapy. Herein, we compared the effects of systemic or local intrauterine injection of bone marrow or adipose-derived mesenchymal stem cells (BMSCs/AMSCs) on the endometrium in a rat model of AS.

Methods

After induction of AS in adult Wistar rats, the CM-Dil-positive BMSCs or AMSCs were injected either locally or intravenously. After 3 weeks, endometrial thickness, collagen deposition, cell migration, and VEGF expression were evaluated using histochemistry/immunofluorescence studies.

Results

In all stem cell-treated groups, an ameliorative effect on the damaged endometrium was noted. Collagen deposition diminished in both groups (IV and local injection) compared to the AS model. In rats injected locally with MSC, fibrosis decreased compared to the other groups. Moreover, endometrial thickness increased in the groups that received local injection of BMSCs and AMSCs more than the IV-transplanted AMSCs group. Immunofluorescent staining demonstrated that although the systemic transplantation of BMSCs was more effective than the other groups on VEGF expression, it led to the lowest number of CM-Dil+ stem cells in the damaged endometrium.

Conclusion

Stem cell transplantation may reconstruct the damaged endometrium, but it is recommended to select the most effective stem cells and injection route. Because the removal of the fibrosis and the replacement of the epithelia cells is an effective therapeutic strategy for AS, in this study, we conclude that the local injection of AMSCs is more appropriate than BMSCs to treat AS.

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References

  1. 1.

    Asherman JG. Amenorrhoea traumatica (atretica). BJOG Int J Obstet Gynaecol. 1948;55(1):23–30.

    CAS  Article  Google Scholar 

  2. 2.

    Westendorp IC, Ankum WM, Mol BW, Vonk J. Prevalence of Asherman’s syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion. Human Reprod. 1998;13(12):3347–50.

  3. 3.

    Conforti A, Alviggi C, Mollo A, De Placido G, Magos A. The management of Asherman syndrome: a review of literature. Reprod Biol Endocrinol. 2013;11(1):118.

    Article  Google Scholar 

  4. 4.

    Yu D, Li T-C, Xia E, Huang X, Liu Y, Peng X. Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman’s syndrome. Fertil Steril. 2008;89(3):715–22.

    Article  Google Scholar 

  5. 5.

    Gargett CE, Schwab KE, Deane JA. Endometrial stem/progenitor cells: the first 10 years. Hum Reprod Update. 2016;22(2):137–63.

    CAS  PubMed  Google Scholar 

  6. 6.

    Queckborner S, Davies LC, von Grothusen C, Santamaria X, Simon C, Gemzell-Danielsson K. Cellular therapies for the endometrium: an update. Acta Obstet Gynecol Scand. 2019;98(5):672–7.

    Article  Google Scholar 

  7. 7.

    Ersoy GS, 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  Google Scholar 

  8. 8.

    Santamaria X, Cabanillas S, Cervello I, Arbona C, Raga F, Ferro J, et al. Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman's syndrome and endometrial atrophy: a pilot cohort study. Hum Reprod. 2016;31(5):1087–96.

    CAS  Article  Google Scholar 

  9. 9.

    Saribas GS, Ozogul C, Tiryaki M, Pinarli FA, Kilic SH. Effects of uterus derived mesenchymal stem cells and their exosomes on Asherman’s syndrome. Acta Histochem. 2020;122(1):151465.

  10. 10.

    Gao L, Huang Z, Lin H, Tian Y, Li P, Lin S. Bone marrow mesenchymal stem cells (BMSCs) restore functional endometrium in the rat model for severe Asherman syndrome. Reprod Sci. 2019;26(3):436–44.

    CAS  Article  Google Scholar 

  11. 11.

    Kilic S, Yuksel B, Pinarli F, Albayrak A, Boztok B, Delibasi T. Effect of stem cell application on Asherman syndrome, an experimental rat model. J Assist Reprod Genet. 2014;31(8):975–82.

    Article  Google Scholar 

  12. 12.

    Zhao G, Cao Y, Zhu X, Tang X, Ding L, Sun H, Li J, Li X, Dai C, Ru T, Zhu H, Lu J, Lin C, Wang J, Yan G, Wang H, Wang L, Dai Y, Wang B, Li R, Dai J, Zhou Y, Hu Y. Transplantation of collagen scaffold with autologous bone marrow mononuclear cells promotes functional endometrium reconstruction via downregulating ΔNp63 expression in Asherman's syndrome. Sci China Life Sci. 2017;60(4):404–16.

  13. 13.

    Noel D, Caton D, Roche S, Bony C, Lehmann S, Casteilla L, et al. Cell specific differences between human adipose-derived and mesenchymal-stromal cells despite similar differentiation potentials. Exp Cell Res. 2008;314(7):1575–84. https://doi.org/10.1016/jyexcr200712022 Epub 2008 Jan 12.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Zhu X, Shi W, Tai W, Liu F. The comparition of biological characteristics and multilineage differentiation of bone marrow and adipose derived mesenchymal stem cells. Cell Tissue Res. 2012;350(2):277–87. https://doi.org/10.1007/s00441-012-1453-1 Epub 2012 Jun 5.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    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  Google Scholar 

  16. 16.

    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. https://doi.org/10.1371/journalpone0096662 eCollection 2014.

    Article  PubMed  Google Scholar 

  17. 17.

    Shao X, Ai G, Wang L, Qin J, Li Y, Jiang H, et al. Adipose-derived stem cells transplantation improves endometrial injury repair. Zygote. 2019;27(6):367–74. https://doi.org/10.1017/S096719941900042X Epub 2019 Aug 27.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Hadi AM, Mouchaers KTB, Schalij I, Grunberg K, Meijer GA, Vonk-Noordegraaf A, et al. Rapid quantification of myocardial fibrosis: a new macro-based automated analysis. Cell Oncol. 2010;34(4):343–54.

    Article  Google Scholar 

  19. 19.

    Monsef F, Artimani T, Alizadeh Z, Mahdi R, Solgi G, Yavangi M, et al. Effects of adipose- derived stromal vascular fraction on Asherman syndrome model. Acta Histochem. 2020;122(5):151556.

    CAS  Article  Google Scholar 

  20. 20.

    Koohestani F, Braundmeier AG, Mahdian A, Seo J, Bi J, Nowak RA. Extracellular matrix collagen alters cell proliferation and cell cycle progression of human uterine leiomyoma smooth muscle cells. PLoS One. 2013;8(9):e75844. https://doi.org/10.1371/journalpone0075844 eCollection 2013.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Gargett CE, Masuda H. Adult stem cells in the endometrium. Mol Hum Reprod. 2010;16(11):818–34. https://doi.org/10.1093/molehr/gaq061 Epub 2010 Jul 13.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Hu J, Yuan R. The expression levels of stem cell markers importin13, c-kit, CD146, and telomerase are decreased in endometrial polyps. Med Sci Monit. 2011;17(8):BR221–7. https://doi.org/10.12659/msm881901.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Domnina A, Novikova P, Obidina J, Fridlyanskaya I, Alekseenko L, Kozhukharova I, et al. Human mesenchymal stem cells in spheroids improve fertility in model animals with damaged endometrium. Stem Cell Res Ther. 2018;9(1):50. https://doi.org/10.1186/s13287-018-0801-9.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    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):3324–31.

    CAS  Article  Google Scholar 

  25. 25.

    Malhotra N, Bahadur A, Kalaivani M, Mittal S. Changes in endometrial receptivity in women with Asherman’s syndrome undergoing hysteroscopic adhesiolysis. Arch Gynecol Obstet. 2012;286(2):525–30. https://doi.org/10.1007/s00404-012-2336-0 Epub 2012 Apr 26.

    Article  PubMed  Google Scholar 

  26. 26.

    Unger JB, Meeks GR. Hysterectomy after endometrial ablation. Am J Obstet Gynecol. 1996;175(6):1432–6; discussion 1436–7. https://doi.org/10.1016/s0002-9378(96)70086-8.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Su J, Li ZQ, Cui S, Ji LH, Chai KX, Geng H, et al. The expressions of VEGF and VEGFR signaling pathway in the bone marrow mononuclear cells with chronic mountain sickness. Zhonghua Yi Xue Za Zhi. 2018;98(14):1088–92. https://doi.org/10.3760/cmajissn0376-2491201814008.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Li J, Zhang YP, Kirsner RS. Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix. Microsc Res Tech. 2003;60(1):107–14.

    CAS  Article  Google Scholar 

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Acknowledgments

This study was supported by the Hamadan University of Medical Sciences (9804042566).

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Correspondence to Sara Soleimani Asl.

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Monsef, F., Artimani, T., Alizadeh, Z. et al. Comparison of the regenerative effects of bone marrow/adipose-derived stem cells in the Asherman model following local or systemic administration. J Assist Reprod Genet (2020). https://doi.org/10.1007/s10815-020-01856-w

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Keywords

  • Asherman’s syndrome
  • Bone marrow-derived mesenchymal stem cell
  • Adipose-derived mesenchymal stem cell
  • Endometrium