Skip to main content

Advertisement

SpringerLink
Log in

Exosomes Derived from Adipose Mesenchymal Stem Cells Restore Functional Endometrium in a Rat Model of Intrauterine Adhesions

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

Abstract

Intrauterine adhesion (IUA) caused by endometrial injury is one of the important causes of infertility in women of reproductive age and requires advanced treatment strategies. Increasing evidence suggests that the therapeutic effects of mesenchymal stem cells (MSC) mainly depend on their capacity to secrete paracrine factors and are mediated by MSC-derived exosomes. This study aimed to identify exosomes derived from adipose-derived mesenchymal stem cells (ADSC-exo) and explore the therapeutic potential in IUA rat models. ADSC-exo exhibited classic cup-shaped morphology with a positive expression of Alix and CD63 and were mainly concentrated at 109.5 nm. In IUA model, treatment with ADSC-exo maintained normal uterine structure, promoted endometrial regeneration and collagen remodeling, and enhanced the expression of integrin-β3, LIF, and VEGF. An improved receptivity of the regenerated endometrium was confirmed. Our findings demonstrated that ADSC-exo promoted endometrial regeneration and fertility restoration. It suggested that topical administration of ADSC-exo in uterus could be a promising strategy for patients suffering severe intrauterine adhesions and infertility.

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. Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome--one century later. Fertil Steril. 2008;89(4):759–79.

    Article  PubMed  Google Scholar 

  2. Lin YH, Jang TN, Hwang JL, et al. Bacterial colonization with balloon uterine stent placement in the uterus for 30 days: a randomized controlled clinical trial. Fertil Steril. 2015;103(2):513–8.e2.

    Article  PubMed  Google Scholar 

  3. Myers EM, Hurst BS. Comprehensive management of severe Asherman syndrome and amenorrhea. Fertil Steril. 2012;97(1):160–4.

    Article  PubMed  Google Scholar 

  4. Capella-Allouc S, Morsad F, Rongieres-Bertrand C, Taylor S, Fernandez H. Hysteroscopic treatment of severe Asherman’s syndrome and subsequent fertility. Hum Reprod. 1999;14(5):1230–3.

    Article  CAS  PubMed  Google Scholar 

  5. Liu L, Yang H, Guo Y, Yang G, Chen Y. The impact of chronic endometritis on endometrial fibrosis and reproductive prognosis in patients with moderate and severe intrauterine adhesions: a prospective cohort study. Fertil Steril. 2019;111(5):1002–1010.e2.

    Article  PubMed  Google Scholar 

  6. Bosteels J, Weyers S, D'Hooghe TM, et al. Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility. Cochrane Database Syst Rev. 2017;11:CD011110.

    PubMed  Google Scholar 

  7. Makker A, Singh MM. Endometrial receptivity: clinical assessment in relation to fertility, infertility, and antifertility. Med Res Rev. 2006;26(6):699–746.

    Article  CAS  PubMed  Google Scholar 

  8. Simon C, Martin JC, Pellicer A. Paracrine regulators of implantation. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14(5):815–26.

    Article  CAS  PubMed  Google Scholar 

  9. Chi Y, He P, Lei L, Lan Y, Hu J, Meng Y, et al. Transdermal estrogen gel and oral aspirin combination therapy improves fertility prognosis via the promotion of endometrial receptivity in moderate to severe intrauterine adhesion. Mol Med Rep. 2018;17(5):6337–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  PubMed  Google Scholar 

  11. 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  CAS  Google Scholar 

  12. Johnson TV, Bull ND, Martin KR. Identification of barriers to retinal engraftment of transplanted stem cells. Invest Ophthalmol Vis Sci. 2010;51(2):960–70.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Xue J, Li X, Lu Y, Gan L, Zhou L, Wang Y, et al. Gene-modified mesenchymal stem cells protect against radiation-induced lung injury. Mol Ther. 2013;21(2):456–65.

    Article  CAS  PubMed  Google Scholar 

  14. Xu S, Liu C, Ji HL. Concise review: therapeutic potential of the mesenchymal stem cell derived secretome and extracellular vesicles for radiation-induced lung injury: progress and hypotheses. Stem Cells Transl Med. 2019;8(4):344–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tsuji K, Kitamura S, Wada J. Secretomes from mesenchymal stem cells against acute kidney injury: possible heterogeneity. Stem Cells Int. 2018;2018:8693137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Tan JL, Lau SN, Leaw B, Nguyen HPT, Salamonsen LA, Saad MI, et al. Amnion epithelial cell-derived exosomes restrict lung injury and enhance endogenous lung repair. Stem Cells Transl Med. 2018;7(2):180–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang Q, Sun J, Huang Y, Bu S, Guo Y, Gu T, et al. Human amniotic epithelial cell-derived exosomes restore ovarian function by transferring microRNAs against apoptosis. Mol Ther Nucleic Acids. 2019;16:407–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Kurian NK, Modi D. Extracellular vesicle mediated embryo-endometrial cross talk during implantation and in pregnancy. J Assist Reprod Genet. 2019;36(2):189–98.

    Article  Google Scholar 

  19. Freitas D, Balmana M, Pocas J, et al. Different isolation approaches lead to diverse glycosylated extracellular vesicle populations. J Extracell Vesicles. 2019;8(1):1621131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ebrahim N, Mostafa O, El DR, et al. Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model. Stem Cell Res Ther. 2018;9(1):175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Mathew B, Ravindran S, Liu X, Torres L, Chennakesavalu M, Huang CC, et al. Mesenchymal stem cell-derived extracellular vesicles and retinal ischemia-reperfusion. Biomaterials. 2019;197:146–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kong D, Zhang L, Xu X, Zhang J, Li Y, Huang X, et al. Small intestine submucosa is a potential material for intrauterine adhesions treatment in a rat model. Gynecol Obstet Investig. 2018;83(5):499–507.

    Article  CAS  Google Scholar 

  23. Wang J, Ju B, Pan C, Gu Y, Zhang Y, Sun L, et al. Application of bone marrow-derived mesenchymal stem cells in the treatment of intrauterine adhesions in rats. Cell Physiol Biochem. 2016;39(4):1553–60.

    Article  CAS  PubMed  Google Scholar 

  24. Basu J, Ludlow JW. Exosomes for repair, regeneration and rejuvenation. Expert Opin Biol Ther. 2016;16(4):489–506.

    Article  CAS  PubMed  Google Scholar 

  25. Staff NP, Jones DT, Singer W. Mesenchymal stromal cell therapies for neurodegenerative diseases. Mayo Clin Proc. 2019;94(5):892–905.

    Article  PubMed  Google Scholar 

  26. Wu J, Kuang L, Chen C, et al. miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials. 2019;206:87–100.

    Article  CAS  PubMed  Google Scholar 

  27. Evans-Hoeker EA, Young SL. Endometrial receptivity and intrauterine adhesive disease. Semin Reprod Med. 2014;32(5):392–401.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;3(4):e1886.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Akram KM, Samad S, Spiteri MA, Forsyth NR. Mesenchymal stem cells promote alveolar epithelial cell wound repair in vitro through distinct migratory and paracrine mechanisms. Respir Res. 2013;14:9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cervello I, Gil-Sanchis C, Santamaria X, et al. Human CD133(+) bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome. Fertil Steril. 2015;104(6):1552–60.e1–3.

    Article  PubMed  Google Scholar 

  32. Craciunas L, Gallos I, Chu J, et al. Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Hum Reprod Update. 2019;25(2):202–23.

    Article  CAS  PubMed  Google Scholar 

  33. Thomas K, Thomson A, Wood S, Kingsland C, Vince G, Lewis-Jones I, et al. Endometrial integrin expression in women undergoing in vitro fertilization and the association with subsequent treatment outcome. Fertil Steril. 2003;80(3):502–7.

    Article  PubMed  Google Scholar 

  34. Serafini PC, Silva ID, Smith GD, et al. Endometrial claudin-4 and leukemia inhibitory factor are associated with assisted reproduction outcome. Reprod Biol Endocrinol. 2009;7:30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Salleh N, Giribabu N. Leukemia inhibitory factor: roles in embryo implantation and in nonhormonal contraception. ScientificWorldJournal. 2014;2014:201514.

    PubMed  PubMed Central  Google Scholar 

  36. Sugino N, Kashida S, Karube-Harada A, Takiguchi S, Kato H. Expression of vascular endothelial growth factor (VEGF) and its receptors in human endometrium throughout the menstrual cycle and in early pregnancy. Reproduction. 2002;123(3):379–87.

    Article  CAS  PubMed  Google Scholar 

  37. Schlaff WD, Hurst BS. Preoperative sonographic measurement of endometrial pattern predicts outcome of surgical repair in patients with severe Asherman’s syndrome. Fertil Steril. 1995;63(2):410–3.

    Article  CAS  PubMed  Google Scholar 

  38. Hunter RN, Nevitt CD, Gaskins JT, et al. Adipose-derived stromal vascular fraction cell effects on a rodent model of thin endometrium. PLoS One. 2015;10(12):e0144823.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lopatina T, Bruno S, Tetta C, et al. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal. 2014;12:26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hoshino D, Kirkbride KC, Costello K, Clark ES, Sinha S, Grega-Larson N, et al. Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep. 2013;5(5):1159–68.

    Article  CAS  PubMed  Google Scholar 

  41. Hu G, Drescher KM, Chen XM. Exosomal miRNAs: biological properties and therapeutic potential. Front Genet. 2012;3:56.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bidarimath M, Khalaj K, Kridli RT, et al. Extracellular vesicle mediated intercellular communication at the porcine maternal-fetal interface: a new paradigm for conceptus-endometrial cross-talk. Sci Rep. 2017;7:40476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank the Pharmacology Department, Basic Medical College, Hebei Medical University.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81471418).

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China

    Shuangdan Zhao, Wenbo Qi, Jiahua Zheng, Yanpeng Tian, Xuejun Qi, Desheng Kong, Jingkun Zhang & Xianghua Huang

Authors
  1. Shuangdan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenbo Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiahua Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanpeng Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xuejun Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Desheng Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jingkun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xianghua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xianghua Huang.

Ethics declarations

This study was approved by the Animal Care and Use Committee of Hebei Medical University. All animal-handling procedures were carried out according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH publication no. 85–23, revised 1996).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, S., Qi, W., Zheng, J. et al. Exosomes Derived from Adipose Mesenchymal Stem Cells Restore Functional Endometrium in a Rat Model of Intrauterine Adhesions. Reprod. Sci. 27, 1266–1275 (2020). https://doi.org/10.1007/s43032-019-00112-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-019-00112-6

Keywords

Search

Navigation