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Successful orthotopic uterine allotransplantation in a rabbit model using aorta and cava anastomoses: a short-term viability study

  • Yu Liu
  • Ying Zhang
  • Yan Ding
  • Junwei Li
  • Qunye Tang
  • Xuyin Zhang
  • Keqin HuaEmail author
General Gynecology
  • 14 Downloads

Abstract

Purposes

We aim to develop a rabbit model system for studies on uterus transplantation.

Methods

Six sexually mature female New Zealand white rabbits of proven fertility were used for harvesting the uterine allograft with an aortic-caval macrovascular patch (including the aorta, inferior vena cava, common and internal iliacs, and uterine arterial and venous tree). The patches were transplanted in the six recipients orthotopically using aorta and cava anastomoses. Tacrolimus (0.5 mg twice daily, p.o.) was administered postoperatively for immunosuppression.

Results

Surgical survival was 100% (n = 6), and the graft survival rate was 83.3% (n = 5). No rabbits died intraoperatively, but only one achieved short-term survival (for 8 days). Four rabbits (#1, #2, #3 and #4) died within the first 24 h as a result of veno-vena anastomosis breakdown, bradycardia, intestinal necrosis, and respiratory failure, respectively. Rabbits #5 (30 h) and #6 (8 days) died from intestinal obstruction and pneumonia, respectively. Uterine morphology was normal in rabbit #6, and rejection was not observed in the grafted uterus, which was further verified by H&E and immunohistochemistry.

Conclusions

Aorta and cava anastomoses can be used to ensure a viable transplanted uterus by reconstructing an adequate blood supply to the transplanted uterine graft in a rabbit model. We have demonstrated the feasibility of tacrolimus monotherapy in suppressing the rejection of an allotransplanted uterus in a rabbit model. However, UTx in a rabbit model seems difficult to achieve long-term survival.

Keywords

Orthotopic uterine allotransplantation Aorto-caval anastomosis Rabbit model Immunosuppression Short term 

Abbreviations

AA

Abdominal aorta

ABS

Acrylonitrile butadiene styrene

ARRIVE

Animal research: reporting in vivo experiments

AUFI

Absolute uterine factor infertility

FIGO

The International Federation of Gynecology and Obstetrics

H&E

Hematoxylin and eosin

IVC

Inferior vena cave

NC3Rs

The National Centre for the 3Rs

PGA

Polyglycolic acid absorbable sutures

UTx

Uterus transplantation

Notes

Acknowledgements

The authors would like to thank the staff at Sapphire Veterinary Hospital and the veterinarians at the Institute of Neuroscience of Shanghai Institutes for Biological Sciences, CAS (Shanghai, China), who worked tirelessly at helping us to carry out our transplant work.

Author contributions

YL participated in the conception of the work and the performance of the surgery and the writing of the paper; YZ participated in the performance of the surgery and revising the manuscript; YD participated in the performance of the surgery; JL participated in the performance of the surgery; QT contributed new reagents and helped in data analysis; XZ helped in surgery design and revising the manuscript; KH participated in design of the work and revised it critically for important intellectual content and gave the final approval of the version to be published.

Funding

There is no research funding for this work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants; informed consent statement is not applicable.

References

  1. 1.
    Brannstrom M, Dahm KP, Greite R, Molne J, Diaz-Garcia C, Tullius SG (2018) Uterus transplantation: a rapidly expanding field. Transplantation 102:569–577.  https://doi.org/10.1097/TP.0000000000002035 CrossRefPubMedGoogle Scholar
  2. 2.
    Brannstrom M, Johannesson L, Bokstrom H, Kvarnstrom N, Molne J, Dahm-Kahler P, Enskog A, Milenkovic M, Ekberg J, Diaz-Garcia C, Gabel M, Hanafy A, Hagberg H, Olausson M, Nilsson L (2015) Livebirth after uterus transplantation. Lancet 385:607–616.  https://doi.org/10.1016/S0140-6736(14)61728-1 CrossRefPubMedGoogle Scholar
  3. 3.
    Ejzenberg D, Andraus W, Baratelli CML, Ducatti L, Song A, Tanigawa R, Rocha-Santos V, Macedo AR, Soares JJ, Serafini PC, Bertocco DPHL, Pulcinelli FR, Carneiro DL, Chada BE (2019) Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility. Lancet 392:2697–2704.  https://doi.org/10.1016/S0140-6736(18)31766-5 CrossRefPubMedGoogle Scholar
  4. 4.
    Kisu I, Liu Y, Chen G, Song MJ, Chang CY, Koon TH, Banno K, Aoki D (2019) Current progress in uterus transplantation research in Asia. J Clin Med.  https://doi.org/10.3390/jcm8020245 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tardieu A, Dion L, Lavoue V, Chazelas P, Marquet P, Piver P, Sallee C, Aubard Y, Barin-Le GC, Favreau F, Gauthier T (2019) The key role of warm and cold ischemia in uterus transplantation: a review. J Clin Med.  https://doi.org/10.3390/jcm8060760 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Racho ER, Wranning CA, Molne J, Kurlberg G, Brannstrom M (2003) Pregnancy in transplanted mouse uterus after long-term cold ischaemic preservation. Hum Reprod 18:2024–2030.  https://doi.org/10.1093/humrep/deg395 CrossRefGoogle Scholar
  7. 7.
    Diaz-Garcia C, Johannesson L, Shao R, Bilig H, Brannstrom M (2014) Pregnancy after allogeneic uterus transplantation in the rat: perinatal outcome and growth trajectory. Fertil Steril 102:1545–1552.  https://doi.org/10.1016/j.fertnstert.2014.09.010 CrossRefPubMedGoogle Scholar
  8. 8.
    Saso S, Petts G, Chatterjee J, Thum MY, David AL, Corless D, Boyd M, Noakes D, Lindsay I, Del PG, Ghaem-Maghami S, Smith JR (2014) Uterine allotransplantation in a rabbit model using aorto-caval anastomosis: a long-term viability study. Eur J Obstet Gynecol Reprod Biol 182:185–193.  https://doi.org/10.1016/j.ejogrb.2014.09.029 CrossRefPubMedGoogle Scholar
  9. 9.
    Scott JR, Anderson WR, Kling TG, Yannone ME (1970) Uterine transplantation in dogs. Gynecol Investig 1:140–148CrossRefGoogle Scholar
  10. 10.
    Avison DL, DeFaria W, Tryphonopoulos P, Tekin A, Attia GR, Takahashi H, Jin Y, Palaios E, Pararas N, Carreno MR, Santiago S, Bazer F, Ruiz P, Tzakis A (2009) Heterotopic uterus transplantation in a swine model. Transplantation 88:465–469.  https://doi.org/10.1097/TP.0b013e3181b07666 CrossRefPubMedGoogle Scholar
  11. 11.
    Wei L, Xue T, Yang H, Zhao GY, Zhang G, Lu ZH, Huang YH, Ma XD, Liu HX, Liang SR, Yang F, Chen BL (2013) Modified uterine allotransplantation and immunosuppression procedure in the sheep model. PLoS ONE 8:e81300.  https://doi.org/10.1371/journal.pone.0081300 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kisu I, Banno K, Mihara M, Suganuma N, Aoki D (2013) Current status of uterus transplantation in primates and issues for clinical application. Fertil Steril 100:280–294.  https://doi.org/10.1016/j.fertnstert.2013.03.004 CrossRefPubMedGoogle Scholar
  13. 13.
    Saso S, Petts G, David AL, Thum MY, Chatterjee J, Vicente JS, Marco-Jimenez F, Corless D, Boyd M, Noakes D, Lindsay I, Del PG, Ghaem-Maghami S, Smith JR (2015) Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model. Eur J Obstet Gynecol Reprod Biol 185:164–169.  https://doi.org/10.1016/j.ejogrb.2014.12.017 CrossRefPubMedGoogle Scholar
  14. 14.
    Ramirez ER, Ramirez ND, Nessetti MB, Khatamee M, Wolfson MR, Shaffer TH, Ramirez VZ, Ramirez HA (2011) Pregnancy and outcome of uterine allotransplantation and assisted reproduction in sheep. J Minim Invasive Gynecol 18:238–245.  https://doi.org/10.1016/j.jmig.2010.11.006 CrossRefPubMedGoogle Scholar
  15. 15.
    Sieunarine K, Zakaria FB, Boyle DC, Corless DJ, Noakes DE, Lindsay I, Lawson A, Ungar L, Del PG, Smith JR (2005) Possibilities for fertility restoration: a new surgical technique. Int Surg 90:249–256PubMedGoogle Scholar
  16. 16.
    Gauthier T, Bertin F, Fourcade L, Maubon A, Saint MF, Piver P, Marquet P, Pommepuy I, Plainard X, Couquet C, Cornuejols MJ, Essig M, Aubard Y (2011) Uterine allotransplantation in ewes using an aortocava patch. Hum Reprod 26:3028–3036.  https://doi.org/10.1093/humrep/der288 CrossRefPubMedGoogle Scholar
  17. 17.
    Confino E, Vermesh M, Thomas WJ, Gleicher N (1986) Non-vascular transplantation of the rabbit uterus. Int J Gynaecol Obstet 24:321–325CrossRefGoogle Scholar
  18. 18.
    Sieunarine K, Hakim NS, Corless DJ, Noakes DE, Ungar L, Del PG, Smith JR (2005) Is it feasible to use a large vessel patch with a uterine allograft en bloc for uterine transplantation? Int Surg 90:257–261PubMedGoogle Scholar
  19. 19.
    Saso S, Hurst S, Chatterjee J, Kuzmin E, Thum Y, David AL, Hakim N, Corless DJ, Boyd M, Noakes DE, Lindsay I, Ghaem-Maghami S, Del PG, Smith JR (2014) Test of long-term uterine survival after allogeneic transplantation in rabbits. J Obstet Gynaecol Res 40:754–762.  https://doi.org/10.1111/jog.12256 CrossRefPubMedGoogle Scholar
  20. 20.
    El-Akouri RR, Molne J, Groth K, Kurlberg G, Brannstrom M (2006) Rejection patterns in allogeneic uterus transplantation in the mouse. Hum Reprod 21:436–442.  https://doi.org/10.1093/humrep/dei349 CrossRefPubMedGoogle Scholar
  21. 21.
    Milliez J (2009) Uterine transplantation FIGO committee for the ethical aspects of human reproduction and women’s health. Int J Gynaecol Obstet 106:270.  https://doi.org/10.1016/j.ijgo.2009.03.045 CrossRefGoogle Scholar
  22. 22.
    Brodbelt DC, Blissitt KJ, Hammond RA, Neath PJ, Young LE, Pfeiffer DU, Wood JL (2008) The risk of death: the confidential enquiry into perioperative small animal fatalities. Vet Anaesth Analg 35:365–373.  https://doi.org/10.1111/j.1467-2995.2008.00397.x CrossRefPubMedGoogle Scholar
  23. 23.
    Scholch D, Scholch S, Strahl O, Hoffmann I, Beckmann MW, Dittrich R (2012) Porcine uterus cryopreservation: an analysis of contractile function using different uterotonics. Cryobiology 65:88–92.  https://doi.org/10.1016/j.cryobiol.2012.05.009 CrossRefPubMedGoogle Scholar
  24. 24.
    Wei H (2018) Three-dimensional model reconstruction of abdominal pelvic vascular network in rabbits by micro-CT. Anhui Medical University, Hefei (in Chinese) Google Scholar
  25. 25.
    Halazun KJ, Al-Mukhtar A, Aldouri A, Willis S, Ahmad N (2007) Warm ischemia in transplantation: search for a consensus definition. Transplant Proc 39:1329–1331.  https://doi.org/10.1016/j.transproceed.2007.02.061 CrossRefPubMedGoogle Scholar
  26. 26.
    Feuillu B, Cormier L, Frimat L, Kessler M, Amrani M, Mangin P, Hubert J (2003) Kidney warming during transplantation. Transpl Int 16:307–312.  https://doi.org/10.1007/s00147-003-0549-7 CrossRefPubMedGoogle Scholar
  27. 27.
    Diaz-Garcia C, Akhi SN, Martinez-Varea A, Brannstrom M (2013) The effect of warm ischemia at uterus transplantation in a rat model. Acta Obstet Gynecol Scand 92:152–159.  https://doi.org/10.1111/aogs.12027 CrossRefPubMedGoogle Scholar
  28. 28.
    Adachi M, Kisu I, Nagai T, Emoto K, Banno K, Umene K, Nogami Y, Tsuchiya H, Itagaki I, Kawamoto I, Nakagawa T, Ogasawara K, Aoki D (2016) Evaluation of allowable time and histopathological changes in warm ischemia of the uterus in cynomolgus monkey as a model for uterus transplantation. Acta Obstet Gynecol Scand 95:991–998.  https://doi.org/10.1111/aogs.12943 CrossRefPubMedGoogle Scholar
  29. 29.
    Brannstrom M, Johannesson L, Dahm-Kahler P, Enskog A, Molne J, Kvarnstrom N, Diaz-Garcia C, Hanafy A, Lundmark C, Marcickiewicz J, Gabel M, Groth K, Akouri R, Eklind S, Holgersson J, Tzakis A, Olausson M (2014) First clinical uterus transplantation trial: a six-month report. Fertil Steril 101:1228–1236.  https://doi.org/10.1016/j.fertnstert.2014.02.024 CrossRefPubMedGoogle Scholar
  30. 30.
    He X, Yan Q, Wan X, Xi X, Wu X, Tang X (2006) Observation of the acute rejection of allograft uterine transplantation in rat. Chin J Organ Transplant 27(03):181–183 (in Chinese)Google Scholar
  31. 31.
    Akhi SN, Diaz-Garcia C, El-Akouri RR, Wranning CA, Molne J, Brannstrom M (2013) Uterine rejection after allogeneic uterus transplantation in the rat is effectively suppressed by tacrolimus. Fertil Steril 99:862–870.  https://doi.org/10.1016/j.fertnstert.2012.11.002 CrossRefPubMedGoogle Scholar
  32. 32.
    Groth K, Akhi SN, Molne J, Wranning CA, Brannstrom M (2012) Effects of immunosuppression by cyclosporine A on allogenic uterine transplant in the rat. Eur J Obstet Gynecol Reprod Biol 163:97–103.  https://doi.org/10.1016/j.ejogrb.2012.03.026 CrossRefPubMedGoogle Scholar
  33. 33.
    Cheng P, Zhong L, Jiang Z, Wang Y, Pan M, Gao YI (2015) High-dose immunosuppressant alters the immunological status of New Zealand white rabbits following skin transplantation. Exp Ther Med 10:1003–1008.  https://doi.org/10.3892/etm.2015.2608 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Johannesson L, Enskog A, Molne J, Diaz-Garcia C, Hanafy A, Dahm-Kahler P, Tekin A, Tryphonopoulos P, Morales P, Rivas K, Ruiz P, Tzakis A, Olausson M, Brannstrom M (2013) Preclinical report on allogeneic uterus transplantation in non-human primates. Hum Reprod 28:189–198.  https://doi.org/10.1093/humrep/des381 CrossRefPubMedGoogle Scholar
  35. 35.
    Kisu I, Mihara M, Banno K, Hara H, Masugi Y, Araki J, Iida T, Yamada Y, Kato Y, Shiina T, Suganuma N, Aoki D (2014) Uterus allotransplantation in cynomolgus macaque: a preliminary experience with non-human primate models. J Obstet Gynaecol Res 40:907–918.  https://doi.org/10.1111/jog.12302 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of GynecologyThe Obstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
  2. 2.Department of UrologyZhongshan Hospital, Fudan UniversityShanghaiChina
  3. 3.Shanghai Key Laboratory of Organ TransplantationShanghaiChina

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