Date: 6th July 2020
Article in brief:
The uterus is a crucial component of the female reproductive system and supports many of the complex biological functions that are essential for mammalian reproduction. Approximately 6% of women undergoing infertility treatments have a dysfunctional uterus and whilst uterine transplants have shown clinical promise, fewer than 10 babies have resulted from such procedures in the US. Now scientists have bioengineered uterine tissue to restore uterine structure and function in rabbits, supporting foetal development through to live births.
Using autologous primary cells seeded onto biodegradable scaffolds to restore the function of relatively ‘simple’ organs such as the urethra and bladder in human patients has been performed. However, a complex organ such as the uterus requires a higher functional capacity in order to support embryo implantation, foetal development and nourishment, and contractions during birth. Now scientists from the Wake Forest University School of Medicine, US, led by Anthony Atala, have used biodegradable polymer scaffolds seeded with autologous cells to restore uterine structure and function in rabbits – a popular large animal model for the reproductive system.
The team started by using biodegradable polymer scaffolds, 6–8 cm in length and 2.5 cm in width, composed of poly-dl-lactide-coglycolide (PLGA)-coated polyglycolic acid (PGA) seeded with rabbit primary uterine-derived cells.
- PGA/PLGA scaffolds were tailor-made into semicircular shapes; the outer layer was seeded with 10 million cells/ cm2 derived from the myometrium, whilst the inside of the scaffold was seeded with 10 million cells/ cm2 of endometrium-derived cells.
- Rabbits possess two separated functional uterine horns and cervices, each with a capacity to carry a pregnancy. Rabbits underwent a full excision of one uterine horn and a subtotal excision of the remaining uterine horn in order to provide a working model for transplantation of the engineered uterus.
- Uterine devices with or without seeded cells were transplanted into the remaining partially excised horn.
- Just under half the animals were sacrificed at 1, 3 or 6 months post-implantation (PI) and were examined for abnormalities and repair.
- At 6 months, the control groups, which had uterine horn excision but no device transplant, had areas of exposed endometrium and fibrotic scars along the surgical excision site.
- Meanwhile, the tissue-engineered group had patent cavities with a preserved uterine configuration resembling the uteri of control animals.
- The group of rabbits transplanted with the unseeded uterus had multiple filling defects of the endometrium and marked strictures along the lumen of the implanted uterine horn.
- Further histological analysis showed that by 6 months PI, only the tissue-engineered group showed no obvious histologic boundaries between the native tissue and the device, and reconstruction of all uterine tissue layers, including a vascularised endometrium with secretory gland structures and a two-layered myometrium.
- To investigate the in vivo functionality of the engineered uterine tissue, the team conducted reproductive studies in the remaining group of animals.
- Only the rabbits receiving the tissue-engineered constructs had normal pregnancies (4/10) inside the reconstructed segment of the uterus.
- The engineered uteri supported normal foetal development as judged by healthy births, with the average delivered foetus body weight comparable to normal controls.
Conclusions and future applications:
Here the team provide strong evidence that an autologous cell-seeded bioengineered uterine construct can be used as a regenerative medicine-based approach to create functional neo-uterine tissue in vivo. The tissue-engineered uteri were functionally, and could respond to the expansion and mechanical strain that occurred during pregnancy, resulting in full-term pregnancies and producing live offspring.
This research is likely to introduce new avenues for treating uterine defects in humans, giving us the ability to create tissue substitutes derived from a patient’s own cells.
Whilst, uteri donors and transplantations are possible, they are rare, and subject to organ shortage and carry the risk of immune rejection. There is much work currently being undertaken on the chronic organ shortage crisis such as developing human-animal hybrid organs or 3D printing of organs such as the human heart. In fact, bioprinting has even entered space in attempts to overcome some of the complexities of creating complex 3D self-supporting structures required to achieve bioprinted organs.
Other low-cost alternatives are also being developed such as electronic-free, glucose-responsive gel technology that can function as an artificial pancreas. However, work remains scarce on solutions to uterine infertility, and the work presented here offers a crucial step forward into finding viable options for those afflicted.
Regenerative medicine and tissue engineering technologies such as this are also an attractive option for overcoming donor organ shortages and immune rejection in general, and the technology presented here offers an interesting opportunity to advance this method into the regeneration of other organs using a different cell types and scaffolds. Whilst, it is likely that bioprinting advances may offer long-term solutions in the next decade or so, tissue-engineering may present a less complex and more near-term solution for many diseases, and offer the ability to regenerate damaged parts of organs rather than replacing it in its entirety.
For more information please read the press release from the Wake Forest University School of Medicine.
Magalhaes, R. S., J. K. Williams, K. W. Yoo, J. J. Yoo and A. Atala (2020). “A tissue-engineered uterus supports live births in rabbits.” Nature Biotechnology.
https://doi.org/10.1038/s41587-020-0547-7
