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A tissue-engineered uterus supports live births in rabbits

Nature Biotechnology volume 38, pages 1280–1287 (2020)Cite this article

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Abstract

Bioengineered uterine tissue could provide a treatment option for women with uterine factor infertility. In large animal models, reconstruction of the uterus has been demonstrated only with xenogeneic tissue grafts. Here we use biodegradable polymer scaffolds seeded with autologous cells to restore uterine structure and function in rabbits. Rabbits underwent a subtotal uterine excision and were reconstructed with autologous cell-seeded constructs, with nonseeded scaffolds or by suturing. At 6 months postimplantation, only the cell-seeded engineered uteri developed native tissue-like structures, including organized luminal/glandular epithelium, stroma, vascularized mucosa and two-layered myometrium. Only rabbits with cell-seeded constructs had normal pregnancies (four in ten) in the reconstructed segment of the uterus and supported fetal development to term and live birth. With further development, this approach may provide a regenerative medicine solution to uterine factor infertility.

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Fig. 1: Construct fabrication and in vivo implantation.
Fig. 2: Histological analysis of Masson’s trichrome-stained cross-sections of reconstructed uterine segments retrieved after surgery.
Fig. 3: Histomorphological analysis of the uterine mucosa at 6 months postimplantation.
Fig. 4: Immunohistochemical staining of functional markers in the tissue-engineered uteri at 6months postimplantation.
Fig. 5: Fetal development site identification at days 29–30 postmating in a single-horn pregnant uterus.

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Data availability

The data that supports the findings of this study are available from the corresponding author, upon reasonable request.

References

  1. Taylor, E. & Gomel, V. The uterus and fertility. Fertil. Steril. 89, 1–16 (2008).

    Article  Google Scholar 

  2. Chan, Y. Y. et al. Reproductive outcomes in women with congenital uterine anomalies: a systematic review. Ultrasound Obstet. Gynecol. 38, 371–382 (2011).

    Article  CAS  Google Scholar 

  3. Abrao, M. S., Muzii, L. & Marana, R. Anatomical causes of female infertility and their management. Int. J. Gynaecol. Obst. 123, S18–S24 (2013).

    Article  Google Scholar 

  4. 2015 Assisted Reproductive Technology National Summary Report https://http://www.cdc.gov/art/pdf/2015-report/ART-2015-National-Summary-Report.pdf (Centers for Disease Control and Prevention, 2017).

  5. Fageeh, W., Raffa, H., Jabbad, H. & Marzouki, A. Transplantation of the human uterus. Int. J. Gynaecol. Obstet. 76, 245–251 (2002).

    Article  CAS  Google Scholar 

  6. Ozkan, O. et al. Preliminary results of the first human uterus transplantation from a multiorgan donor. Fertil. Steril. 99, 470–476 (2013).

    Article  Google Scholar 

  7. Brannstrom, M. et al. The first clinical uterus transplantation trial: a six-month report. Fertil. Steril. 101, https://doi.org/10.1016/j.fertnstert.2014.02.024 (2014).

  8. Brannstrom, M. et al. Livebirth after uterus transplantation. Lancet 385, 607–616 (2015).

    Article  Google Scholar 

  9. Testa, G. et al. First live birth after uterus transplantation in the United States. Am. J. Transplant. 18, 1270–1274 (2018).

    Article  CAS  Google Scholar 

  10. Baptista, P. M. & Atala, A. Regenerative medicine: the hurdles and hopes. Trans. Res. 163, 255–258 (2014).

    Article  Google Scholar 

  11. Atala, A., Bauer, S. B., Soker, S., Yoo, J. J. & Retik, A. B. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 367, 1241–1246 (2006).

    Article  Google Scholar 

  12. L’Heureux, N., McAllister, T. N. & de la Fuente, L. M. Tissue-engineered blood vessel for adult arterial revascularization. N. Engl. J. Med. 357, 1451–1453 (2007).

    Article  Google Scholar 

  13. Olausson, M. et al. Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. Lancet 380, 230–237 (2012).

    Article  Google Scholar 

  14. Raya-Rivera, A. et al. Tissue-engineered autologous urethras for patients who need reconstruction: an observational study. Lancet 377, 1175–1182 (2011).

    Article  Google Scholar 

  15. Raya-Rivera, A. M. et al. Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. Lancet 384, 329–336 (2014).

    Article  Google Scholar 

  16. Campo, H., Cervello, I. & Simon, C. Bioengineering the uterus: an overview of recent advances and future perspectives in reproductive medicine. Ann. Biomed. Eng. 45, 1710–1717 (2017).

    Article  Google Scholar 

  17. Hellstrom, M., Bandstein, S. & Brannstrom, M. Uterine tissue engineering and the future of uterus transplantation. Ann. Biomed. Eng. 45, 1718–1730 (2017).

    Article  Google Scholar 

  18. Ansari, A. H., Gould, K. & Turner, R. J. Segmental uterine horn replacement in rabbit using umbilical vein. Obst. Gynecol. 60, 733–737 (1982).

    CAS  Google Scholar 

  19. Taveau, J. W. et al. Regeneration of uterine horn using porcine small intestinal submucosa grafts in rabbits. J. Invest. Surg. 17, 81–92 (2004).

    Article  Google Scholar 

  20. De Filippo, R. E., Yoo, J. J. & Atala, A. Urethral replacement using cell seeded tubularized collagen matrices. J. Urol. 168, 1789–1792 (2002).

    Article  Google Scholar 

  21. Dorin, R. P., Pohl, H. G., De Filippo, R. E., Yoo, J. J. & Atala, A. Tubularized urethral replacement with unseeded matrices: what is the maximum distance for normal tissue regeneration? World J. Urol 26, 323–326 (2008).

    Article  Google Scholar 

  22. Fischer, B., Chavatte-Palmer, P., Viebahn, C., Navarrete Santos, A. & Duranthon, V. Rabbit as a reproductive model for human health. Reproduction 144, 1–10 (2012).

    Article  CAS  Google Scholar 

  23. Atala, A. et al. Formation of urothelial structures in vivo from dissociated cells attached to biodegradable polymer scaffolds in vitro. J. Urol. 148, 658–662 (1992).

    Article  CAS  Google Scholar 

  24. Oberpenning, F., Meng, J., Yoo, J. J. & Atala, A. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat. Biotechnol. 17, 149–155 (1999).

    Article  CAS  Google Scholar 

  25. De Filippo, R. E., Yoo, J. J. & Atala, A. Engineering of vaginal tissue in vivo. Tissue Eng. 9, 301–306 (2003).

    Article  Google Scholar 

  26. Chen, K. L., Eberli, D., Yoo, J. J. & Atala, A. Bioengineered corporal tissue for structural and functional restoration of the penis. Proc. Natl Acad. Sci. USA 107, 3346–3350 (2010).

    Article  CAS  Google Scholar 

  27. Atala, A. Engineering tissues, organs and cells. J. Tissue Eng. Regen. Med. 1, 83–96 (2007).

    Article  CAS  Google Scholar 

  28. Park, K. R. et al. CD9 is expressed on human endometrial epithelial cells in association with integrins alpha(6), alpha(3) and beta(1). Mol. Human Reprod. 6, 252–257 (2000).

    Article  CAS  Google Scholar 

  29. Cervello, I. et al. Reconstruction of endometrium from human endometrial side population cell lines. PloS ONE 6, e21221 (2011).

    Article  CAS  Google Scholar 

  30. Mosher, A. A. et al. Development and validation of primary human myometrial cell culture models to study pregnancy and labour. BMC Pregnancy Childbirth 13, S7 (2013).

    Article  Google Scholar 

  31. Wooding, F. B. G. Comparative Olacentation: Structures, Functions, and Evolution 185–231 (Springer, 2008).

  32. Jonkman, M. F., Kauer, F. M., Nieuwenhuis, P. & Molenaar, I. Segmental uterine horn replacement in the rat using a biodegradable microporous synthetic tube. Artificial Organs 10, 475–480 (1986).

    Article  CAS  Google Scholar 

  33. Santoso, E. G. et al. Application of detergents or high hydrostatic pressure as decellularization processes in uterine tissues and their subsequent effects on in vivo uterine regeneration in murine models. PloS ONE 9, e103201.

  34. Campbell, G. R. et al. The peritoneal cavity as a bioreactor for tissue engineering visceral organs: bladder, uterus and vas deferens. J. Tissue Eng. Regen. Med. 2, 50–60 (2014).

    Article  Google Scholar 

  35. Li, X. et al. Regeneration of uterine horns in rats by collagen scaffolds loaded with collagen-binding human basic fibroblast growth factor. Biomaterials 32, 8172–8181 (2011).

    Article  CAS  Google Scholar 

  36. Ding, L. et al. Transplantation of bone marrow mesenchymal stem cells on collagen scaffolds for the functional regeneration of injured rat uterus. Biomaterials 35, 4888–4900 (2014).

    Article  CAS  Google Scholar 

  37. Song, T. et al. Regeneration of uterine horns in rats using collagen scaffolds loaded with human embryonic stem cell-derived endometrium-like cells. Tissue Eng. A. 21, 353–361 (2015).

    Article  Google Scholar 

  38. Miyazaki, K. & Maruyama, T. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials 35, 8791–8800 (2014).

    Article  CAS  Google Scholar 

  39. Hellstrom, M. et al. Bioengineered uterine tissue supports pregnancy in a rat model. Fertil. Steril. 106, https://doi.org/10.1016/j.fertnstert.2016.03.048 (2016).

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Acknowledgements

This work was supported by grants from the National Institutes of Health (no. T32-EB014836-05) and the State of North Carolina. We thank J. Kassis for editorial assistance, T. Wang, H.G. Huddlestone and C. Bishop for their initial background contribution to the project and S. Lankford, A.S. Dean, I. Vasutin, T.J. Cockerham, M. Seeds and E.E. Whitaker for technical assistance.

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Authors and Affiliations

  1. Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Renata S. Magalhaes, J. Koudy Williams, Kyung W. Yoo, James J. Yoo & Anthony Atala

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  1. Renata S. Magalhaes
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  2. J. Koudy Williams
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  3. Kyung W. Yoo
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  5. Anthony Atala
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Contributions

A.A. developed the concept of engineering functional autologous uterine tissue constructs. R.S.M., J.K.W., J.J.Y. and A.A. designed all experiments. R.S.M. performed the in vitro experiments and fabricated the bioengineered uterine constructs. R.S.M. and J.K.W. performed in vivo experiments of uterine tissue excision and construct implantation. K.W.Y. performed in vitro experiments and analyzed the data. R.S.M., J.K.W. and A.A. analyzed the data and wrote the manuscript. A.A. provided direction and supervised the project. R.S.M., J.K.W., J.J.Y. and A.A. reviewed and edited the manuscript.

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Correspondence to Anthony Atala.

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Competing interests

Boston Children’s Hospital was assigned the rights to two issued patents, both titled ‘Tissue Engineered Uterus’, no. 7,049,057, filed 15 November 2002, and no. 7,429,490, filed 7 February 2005, with A.A. and J.J.Y. listed as inventors. Based on the remaining patent term and the need for further studies before this technology is used clinically, there are no current or expected financial interests related to these patents.

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Magalhaes, R.S., Williams, J.K., Yoo, K.W. et al. A tissue-engineered uterus supports live births in rabbits. Nat Biotechnol 38, 1280–1287 (2020). https://doi.org/10.1038/s41587-020-0547-7

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