A tissue-engineered uterus supports live births in rabbits

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.

Data availability

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

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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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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.

Corresponding author

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 (2020). https://doi.org/10.1038/s41587-020-0547-7

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