Uterus transplantation and beyond
Mats Brännström, Mats Brännström
Abstract
Uterus transplantation is today the only available treatment for absolute uterine factor infertility which is caused by either congenital/surgical uterine absence or that a present uterus is non-functioning. Structured animal-based research, from rodents to nonhuman primates, was the scientific basis for a successful introduction of uterus transplantation as a clinical procedure. The patient groups for uterus transplantation, the preclinical research and data from the published human cases will be covered herein. During recent years the concept of bioengineering of organs and tissues has emerged. Creation of a bioengineered uterus is in the initial research state, with experiments performed in rodents. The research that has been performed to create a bioengineered uterus will be summarized. In conclusion, uterus transplantation is now a clinical experimental procedure for treatment of uterine factor infertility. In parallel to the establishment of this combined assisted reproduction technique and transplantation procedure as a routine clinical procedure, we predict that uterus bioengineering will develop further towards introduction within the human setting, but that this process will take several years.
Conflict of interest statement
The authors declare that they have no competing interests.
Figures
References
- Fageeh W, Raffa H, Jabbad H, Marzouki A. Transplantation of the human [10] uterus. Int J Gynaecol Obstet. 2002;76:245–51. doi: 10.1016/S0020-7292(01)00597-5.
- Özkan Ö, Akar ME, Özkan Ö, Erdogan O, Hadimioglu N, Yilmaz M, Gunseren F, Cincik M, Pestereli E, Kocak H, Mutlu D, Dinckan A, Gecici O, Bektas G, Suleymanlar G. Preliminary results of the first human uterus transplantation from a multiorgan donor. Fertil sterile. 2013;99:470–6. doi: 10.1016/j.fertnstert.2012.09.035.
- McCulloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, Nicholl J, Balliol Collaboration. Aronson JK, Barkun JS, Blazeby JM, Boutron IC, Campbell WB, Clavien PA, Cook JA, Ergina PL, Feldman LS, Flum DR, Maddern GJ, Nicholl J, Reeves BC, Seiler CM, Strasberg SM, Meakins JL, Ashby D, Black N, Bunker J, Burton M, Campbell M, Chalkidou K, Chalmers I, de Leval M, Deeks J, Ergina PL, Grant A, Gray M, Greenhalgh R, Jenicek M, Kehoe S, Lilford R, Littlejohns P, Loke Y, Madhock R, McPherson K, Meakins J, Rothwell P, Summerskill B, Taggart D, Tekkis P, Thompson M, Treasure T, Trohler U, Vandenbroucke J. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374:1105–12. doi: 10.1016/S0140-6736(09)61116-8.
- Milliez J. Uterine transplantation FIGO committee for the ethical aspects of human reproduction and women’s health. Int J GynaecolObstet. 2009;106:270.
- Brännström M, Diaz-Garcia C, Hanafy A, Olausson M, Tzakis A. Uterus transplantation: animal research and human possibilities. Fertil Steril. 2012;97:1269–76. doi: 10.1016/j.fertnstert.2012.04.001.
- Brännström M, Johannesson L, Bokström H, Kvarnström N, Mölne J, Dahm-Kähler P, Enskog A, Milenkovic M, Ekberg J, Diaz-Garcia C, Gäbel M, Hanafy A, Hagberg H, Olausson M, Nilsson L. Live birth after uterus transplantation. Lancet. 2015;385:607–16. doi: 10.1016/S0140-6736(14)61728-1.
- Sieunarine K, Zakaria FB, Boyle DC, Corless DJ, Noakes DE, Lindsay I, Lawson A, Ungar L, Del Priores G, Smith JR. Possibilities for fertility restoration: a new surgical technique. Int Surg. 2005;90:249–56.
- Brännström M, Wranning CA, Altchek A. Experimental uterus transplantation. Hum Reprod Update. 2010;16:329–45. doi: 10.1093/humupd/dmp049.
- Hanafy H, Diaz-Garcia C, Olausson M, Brännström M. Uterine transplantation: one human case followed by a decade of experimental research in animal models. Aust N Z J Obstet Gynaecol. 2011;51:199–203. doi: 10.1111/j.1479-828X.2010.01283.x.
- Racho El-Akouri R, Kurlberg G, Brännström M. Successful uterine transplantation in the mouse: pregnancy and postnatal development of offspring. Hum Reprod. 2003;18:2018–23. doi: 10.1093/humrep/deg396.
- Racho El-Akouri R, Wranning CA, Mölne J, Kurlberg G, Brännström M. Pregnancy in transplanted mouse uterus after long-term cold ischaemic preservation. Hum Reprod. 2003;18:2024–30. doi: 10.1093/humrep/deg395.
- Racho El-Akouri R, Groth K, Kurlberg G, Mölne J, Brännström M. Rejection patterns in allogeneic uterus transplantation in the mouse. Hum Reprod. 2006;21:436–42. doi: 10.1093/humrep/dei349.
- Groth K, Akouri R, Wranning CA, Mölne J, Brännström M. Rejection of allogenic uterus transplant in the mouse: time-dependent and site-specific infiltration of leukocyte subtypes. Hum Reprod. 2009;24:2746–54. doi: 10.1093/humrep/dep248.
- Wranning CA, Akhi SN, Kurlberg G, Brännström M. Uterus transplantation in the rat: model development, surgical learning and morphological evaluation. Acta Obstet Gynecol Scand. 2008;87:1239–47. doi: 10.1080/00016340802484966.
- Wranning CA, Akhi SN, Diaz-Garcia C, Brännström M. Pregnancy after syngeneic uterus transplantation and spontaneous mating in the rat. Hum Reprod. 2011;26:553–8. doi: 10.1093/humrep/deq358.
- Akhi SN, Diaz-Garcia C, El-Akouri RR, Wranning CA, Mölne J, Brännström M. Uterine rejection after allogeneic uterus transplantation in the rat is effectively suppressed by tacrolimus. Fertil Steril. 2013;99:862–70. doi: 10.1016/j.fertnstert.2012.11.002.
- Wranning CA, El-Akouri RR, Groth K, Mölne J, Parra AK, Brännström M. Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi-allogeneic mouse model. Hum Reprod. 2007;22:372–9. doi: 10.1093/humrep/del410.
- Groth K, Akhi S, Mölne J, Wranning CA, Brännström M. Effects of immunosuppression by cyclosporine A on allogenic uterine transplant in the rat. Eur J Obstet Gynecol Reprod Biol. 2012;163:97–103. doi: 10.1016/j.ejogrb.2012.03.026.
- Diaz-Garcia C, Akhi SN, WallinA, Pellicer A, Brännström M. First report on fertility after allogeneic uterus transplantation. Acta Obstet Gynecol Scand. 2010;89:1491–4. doi: 10.3109/00016349.2010.520688.
- Diaz-Garcia C, Johannesson L, Shao R, Billig H, Brännström M. Pregnancy after allogeneic uterus transplantation in the rat: perinatal outcome and growth trajectory. Fertil Steril. 2014;102:1545–52. doi: 10.1016/j.fertnstert.2014.09.010.
- Dahm-Kähler P, Wranning CA, Lundmark C, Enskog A, Mölne J, Marcickiewicz J, El-Akouri RR, McCracken J, Brännström M. Transplantation of the uterus in the sheep: methodology and early reperfusion events. J Obstet Gynaecol Res. 2008;34:784–93. doi: 10.1111/j.1447-0756.2008.00854.x.
- Wranning CA, Dahm-Kähler P, Mölne J, Nilsson UA, Enskog A, Brännström M. Transplantation of the uterus in the sheep: oxidative stress and reperfusion injury after short-time cold storage”. Fertil Steril. 2008;90:817–26. doi: 10.1016/j.fertnstert.2007.07.1340.
- Wranning CA, Marcickiewicz J, Enskog A, Dahm-Kähler P, Hanafy A, Brännström M. Fertility after autologous ovine uterine-tubal-ovarian transplantation by vascular anastomosis to the external iliac vessels. Hum Reprod. 2010;25:1973–9. doi: 10.1093/humrep/deq130.
- Ramirez ER, Ramirez DK, Pillari VT, Vasquez H, Ramirez HA. Modified uterine transplant procedure in the sheep model. J Minim Invasive Gynecol. 2008;15:311–4. doi: 10.1016/j.jmig.2008.01.014.
- Ramirez ER, Ramirez-Nessetti DK, Nessetti MB, Khatamee M, Wolfson MR, Shaffer TH, Ramirez VZ, Ramirez HA. Pregnancy and outcome of uterine allotransplantation and assisted reproduction in sheep. J Minim Invasive Gynecol. 2011;18:238–45. doi: 10.1016/j.jmig.2010.11.006.
- Wei L, Xue T, Yang H, Zhao GY, Zhang G, Lu ZH, Huang YH, Ma XD, Liu HX, Liang SR, Yang F, Chen BL. Modified uterine allotransplantation and immunosuppression procedure in the sheep model. PLoS One. 2013;8:e81300. doi: 10.1371/journal.pone.0081300.
- Wranning CA, Racho El-Akouri R, Lundmark C, Dahm-Kähler P, Mölne J, Enskog A, Brännström M. Autotransplantation of the uterus in the domestic pig: surgical technique and early reperfusion events. J Obstet Gynaecol Res. 2006;32:358–67. doi: 10.1111/j.1447-0756.2006.00426.x.
- Avison DL, DeFaria W, Tryphonopoulos P, Tekin A, Attia GR, Takahashi H, Jin Y, Palaios E, Pararas N, Carrena MR, Santiago S, Bazer F, Ruiz P, Tzakis A. Heterotopic uterus transplantation in a swine model. Transplantation . 2009;88:465–9. doi: 10.1097/TP.0b013e3181b07666.
- Enskog A, Johannesson L, Chai DC, Dahm-Kähler P, Marcickiewicz J, Nyachieo A, Mwenda JM, Brännström M. Uterus transplantation in the baboon: methodology and long-term function after auto-transplantation. Hum Reprod. 2010;25:1980–7. doi: 10.1093/humrep/deq109.
- Johannesson L, Enskog A, Dahm-Kähler P, Hanafy A, Chai DC, Mwenda JM, Diaz-Garcia C, Olausson M, Brännström M. Uterus transplantation in a non-human primate: long-term follow up after autologous transplantation. Hum Reprod. 2012;27:1640–8. doi: 10.1093/humrep/des093.
- Johannesson L, Enskog A, Mölne J, Diaz-Garcia C, Hanafy A, Dahm-Kähler P, Tekin A, Tryphonopoulos P, Morales P, Rivas K, Ruiz P, Tzakis A, Olausson M, Brännström M. Preclinical report on allogeneic uterus transplantation in non-human primates. Hum Reprod. 2013;28:189–98. doi: 10.1093/humrep/des381.
- Tryphonopoulos P, Tzakis AG, Tekin A, Johannesson L, Rivas K, Morales PR, Wagner J, Mölne J, Enskog A, Diaz-Garcia C, Dahm-Kähler P, Bertho M, Zimberg S, Falcone T, Ruiz P, Olausson M, Brännström M. Allogeneic uterus transplantation in baboons: surgical technique and challenges to long-term graft survival. Transplantation. 2014;98:51–6. doi: 10.1097/TP.0000000000000322.
- Kisu I, Mihara M, Banno K, Hara H, Yamamoto T, Araki J, Iida T, Hayashi Y, Moriquchi H, Aoki D. A new surgical technique of uterine auto-transplantation in cynomolgus monkey: preliminary report about two cases. Arch Gynecol Obstet. 2012;285:129–37. doi: 10.1007/s00404-011-1901-2.
- Mihara M, Kisu I, Hara H, Iida T, Yamamoto T, Araki J, Hayashi Y, Moriguchi H, Narushima M, Banno K, Suganuma N, Aoki D, Koshima I. Uterus autotransplantation in cynomolgus macaques: intraoperative evaluation of uterine blood flow using indocyanine green. Hum Reprod. 2011;26(11):3019–27. doi: 10.1093/humrep/der276.
- Mihara M, Kisu I, Hara H, Iida T, Araki J, Shim T, Narushima M, Yamamoto T, Moriquchi H, Kato Y, Tonsho M, Banno K, Aoki D, Suganuma N, Kagawa N, Takehara Y, Kato O, Koshima I. Uterine autotransplantation in cynomolgus macaques: the first case of pregnancy and delivery. Hum Reprod. 2012;27:2332–40. doi: 10.1093/humrep/des169.
- Kisu I, Banno K, Mihara M, Hara H, Umene K, Adachi M, Nogami Y, Aoki D. A surgical technique using the ovarian vein in non-human primate models of potential living-donor surgery of uterus transplantation. Acta Obstet Gynecol Scand. 2015;94(9):942–8. doi: 10.1111/aogs.12701.
- Kisu I, Mihara M, Banno K, Hara H, Masugi Y, Araki J, Iida T, Yamada Y, Kato Y, Shiina T, Suganuma N, Aoiki D. Uterus allotransplantation in cynomolgus macaque: a preliminary experience with non-human primate models. J Obstet Gynaecol Res. 2014;40:907–18. doi: 10.1111/jog.12302.
- Wranning CA, Mölne J, Racho El-Akouri R, Kurlberg G, Brännstöm M. Short-term ischaemic storage of human uterine myometrium–basic studies towards uterine transplantation. Human Reprod. 2005;20:2736–44. doi: 10.1093/humrep/dei125.
- Del Priore G, Stega J, Sieunarine K, Ungar L, Smith JR. Human uterus retrieval from a multi-organ donor. ObstetGynecol. 2007;109:101–4.
- Gauthier T, Piver P, Pichon N, Bibes R, Guillaudeau A, Piccardo A, Pesteil F, Tricard J, Gardet E, Laskar M, Lalloué F, Marguet P, Aubard Y. Uterus retrieval process from brain dead donors. Fertil Steril. 2014;102:476–82. doi: 10.1016/j.fertnstert.2014.04.016.
- Johannesson L, Diaz-Garcia C, Leonhardt H, Dahm-Kähler P, Marcickiewicz J, Olausson M, Brännström M. Vascular pedicle lengths after hysterectomy: toward future human uterus transplantation. Obstet Gynecol. 2012;119:1219–25. doi: 10.1097/AOG.0b013e318255006f.
- Erman Akar M, Özkan Ö, Aydinuraz B, Dirican K, Cincik M, Mendilcioglu I, Simsek M, Gunseren F, Kocak H, Ciftcioglu A, Gecici O, Özkan Ö. Clinical pregnancy after uterus transplantation. Fertil Steril. 2013;100:1358–63. doi: 10.1016/j.fertnstert.2013.06.027.
- Brännström M, Johannesson L, Dahm-Kähler P, Enskog A, Mölne J, Kvarnström N, Diaz-Garcia C, Hanafy A, Lundmark C, Marcickiewicz J, Gäbel M, Groth K, Akouri R, Holgersson J, Tzakis A, Olausson M. The first clinical uterus transplantation trial: a six months report. Fertil Steril. 2014;101:1228–36. doi: 10.1016/j.fertnstert.2014.02.024.
- Järvholm S, Johannesson L, Brännström M. Psychological aspects in pre-transplantation assessments of patients prior to entering the first uterus transplantation trial. Acta Obstet Gynecol Scand. 2015;94:1035–38. doi: 10.1111/aogs.12696.
- Johannesson L, Kvarnström N, Mölne J, Dahm-Kähler P, Enskog A, Diaz-Garcia C, Olausson M, Brännström M. Uterus transplantation trial: 1-year outcome. Fertil Steril. 2015;103:199–204. doi: 10.1016/j.fertnstert.2014.09.024.
- Järvholm S, Johannesson L, Clarke A, Brännström M. Uterus transplantation trial: psychological evaluation of recipients and partners during the post-transplantation year. Fertil Steril. 2015;104:1010–15. doi: 10.1016/j.fertnstert.2015.06.038.
- Brännström M, Bokström H, Dahm-Kähler P, Diaz-Garcia C, Ekberg J, Enskog A, Hagberg H, Johannesson L, Kvarnström N, Mölne J, Olausson M, Olofsson JI, Rodriguez-Wallberg K. One uterus bridging three generations: first live birth after mother-to-daughter uterus transplantation. Fertil Steril. 2016;106:261–6. doi: 10.1016/j.fertnstert.2016.04.001.
- Azimzadeh AM, Lees JR, Ding Y, Bromberg JS. Immunobiology of transplantation: impact on targets for large and small molecules. Clin Pharmacol Ther. 2011;90:229–42. doi: 10.1038/clpt.2011.106.
- Peloso A, Dhal A, Zambon JP, Li P, Orlando G, Atala A, Soker S. Current achievements and future perspectives in whole-organ bioengineering. Stem Cell Res Ther. 2015;6:107. doi: 10.1186/s13287-015-0089-y.
- Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials. 2011;32:3233–43. doi: 10.1016/j.biomaterials.2011.01.057.
- Hynes RO. The extracellular matrix: not just pretty fibrils. Science. 2009;326:1216–9. doi: 10.1126/science.1176009.
- Lu SH, Wang HB, Liu H, Wang HP, Lin QX, Li DX, Song YX, Duan CM, Feng LX, Wang CY. Reconstruction of engineered uterine tissues containing smooth muscle layer in collagen/matrigel scaffold in vitro. Tissue Eng Part A. 2009;15:1611–8. doi: 10.1089/ten.tea.2008.0187.
- House M, Sanchez CC, Rice WI, Socrates S, Kaplan DL. Cervical tissue engineering using silk scaffolds and human cervical cells. Tissue Eng Part A. 2010;16:2101–12. doi: 10.1089/ten.tea.2009.0457.
- Santoso EG, Yoshida K, Hirota Y, Aizawa M, Yoshino O, Kishida A, Osuga Y, Saito S, Ushida T, Furukawa KS. Application of detergents or high hydrostatic pressure as decellularization processes in uterine tissues and their subsequent effects on in vivo uterine regeration in murine models. PloS One. 2014;9:e103201. doi: 10.1371/journal.pone.0103201.
- Ding L, LI X, Sun H, Su J, Lin N, Peault B, Song T, Yang J, Dai J, Hu Y. Transplantation of bone marro mesenchymal stem cells on collagen scaffolds for the functional regeneration of injured rat uterus. Biomaterials. 2014;35:4888–900. doi: 10.1016/j.biomaterials.2014.02.046.
- Miyazaki K, Maruyama T. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials. 2014;35:8791–800. doi: 10.1016/j.biomaterials.2014.06.052.
- Hellström M, El-Akouri RR, Sihlbom C, Olsson BM, Lengqvist J, Bäckdahl H, Johansson BR, Olausson M, Sumitran-Holgersson S, Brännström M. Towards the development of a bioengineered uterus: comparison of different protocols for rat uterus decellularization. Acta Biomater. 2014;10:5034–42. doi: 10.1016/j.actbio.2014.08.018.
- Hellström M, Norebo.Moya JM, Bandstein S, Bom E, Akouri RR, Miyazaki K, Maruyama T, Brännström M. Bioengineered uterine tissue supports pregnancy in a rat model. Fertil Steril. 2016;106:487–96. doi: 10.1016/j.fertnstert.2016.03.048.
- Scarritt ME, Pashos NC, Bunnell BA. A review of cellularization strategies for tissue engineering of whole organs. Front Bioeng Biotechnol. 2015;3:43. doi: 10.3389/fbioe.2015.00043.
- Hiraoka T, Hirota Y, Saito-Fujita T, Matsuo M, Egashira M, Matsumoto L, Haraguchi H, Dey SK, Furukawa KS, Fujii T, Osuga Y. STAT3 accelerates uterine epithelial regeneration Iin a mouse model of decellularized uterine matrix transplantation. JCI Insight. 2016;1(8) pii: e87591
Source: PubMed