The Bioengineered Uterus: A Possible Future

  • Mats HellströmEmail author
  • Mats Brännström


Customized grafts that include a scaffold populated with the patient’s own cells could become a major advantage in the field of uterus transplantation since it may overcome problematic donor issues and negative side effects from immunosuppression. So far, bioengineering was only utilized to personalize bone structure grafts and less complex organs for clinical use. However, recent tissue engineering protocols developed in animal experiments now include solid tissues and whole organs that were decellularized to create suitable scaffolds for using autologous stem cells in the reconstruction phase. Furthermore, several studies have shown that stratified uterine-like tissues can successfully be created in vitro either from various collagen-derived hydrogels or from decellularized uterine tissues populated with primary cells of the uterus and mesenchymal stem cells. When patches of these constructs were assessed in rodent models, that carried uteri with defect uterine walls, they stimulated regeneration and significantly improved fertility outcomes. Hence, partial uterus repair using a bioengineered construct could potentially become an effective treatment routine to cure infertility or fetal morbidity caused by severe uterus scarring or malformations. However, improved protocols are still needed that will support the construction of a transplantable bioengineered whole uterus. These large constructs must be constructed to enable vascular anastomosis and must facilitate successful implantation and fetal development. Once these objectives are met, this donor option could become a future clinical reality in a uterus transplantation setting.





Extracellular matrix


Embryonic stem (cells)


Green fluorescent protein


High hydrostatic pressure


Induced pluripotent stem (cells)


Mesenchymal stem cells


Sodium dodecyl sulfate


Signal transducer and activator of transcription 3


Uterus transplantation



The authors report no conflict of interest. The work was supported by Wilhelm and Martina Lundgren research foundation, Hjalmar Svensson research foundation, Adlerbertska research foundation, the Swedish Government LUA grant, Wallenberg Foundation and the Swedish Science Research Council (Vetenskapsrådet; Grant No. 116008).


  1. Anasiz Y, Ozgul RK, Uckan-Cetinkaya D. A new chapter for mesenchymal stem cells: decellularized extracellular matrices. Stem Cell Rev Rep. 2017;13(5):587–97.PubMedCrossRefGoogle Scholar
  2. Arnold JT, Kaufman DG, Seppala M, Lessey BA. Endometrial stromal cells regulate epithelial cell growth in vitro: a new co-culture model. Hum Reprod. 2001;16:836–45.PubMedCrossRefGoogle Scholar
  3. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367:1241–6.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. Badylak SF, Taylor D, Uygun K. Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu Rev Biomed Eng. 2011;13:27–53.PubMedCrossRefGoogle Scholar
  6. Benbrook DM, Lightfoot S, Ranger-Moore J, Liu T, Chengedza S, Berry WL, Dozmorov I. Gene expression analysis of biological systems driving an organotypic model of endometrial carcinogenesis and chemoprevention. Gene Regul Syst Biol. 2008;2:21–42.Google Scholar
  7. Borger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, Giebel B. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci. 2017;18PubMedCentralCrossRefGoogle Scholar
  8. Brännström 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. First clinical uterus transplantation trial: a six-month report. Fertil Steril. 2014;101:1228–36.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Brännström 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. Livebirth after uterus transplantation. Lancet. 2015;385:607–16.CrossRefPubMedGoogle Scholar
  10. Campbell GR, Turnbull G, Xiang L, Haines M, Armstrong S, Rolfe BE, Campbell JH. The peritoneal cavity as a bioreactor for tissue engineering visceral organs: bladder, uterus and vas deferens. J Tissue Eng Regen Med. 2008;2:50–60.PubMedCrossRefGoogle Scholar
  11. Campo H, Baptista PM, Lopez-Perez N, Faus A, Cervello I, Simon C. De- and recellularization of the pig uterus: a bioengineering pilot study. Biol Reprod. 2017a;96:34–45.PubMedCrossRefGoogle Scholar
  12. Campo H, Cervello I, Simon C. Bioengineering the uterus: an overview of recent advances and future perspectives in reproductive medicine. Ann Biomed Eng. 2017b;45:1710–7.PubMedCrossRefGoogle Scholar
  13. Cervello I, Gil-Sanchis C, Santamaria X, Cabanillas S, Diaz A, Faus A, Pellicer A, Simon C. Human CD133(+) bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome. Fertil Steril. 2015a;104:1552–60.e1–3.CrossRefGoogle Scholar
  14. Cervello I, Santamaria X, Miyazaki K, Maruyama T, Simon C. Cell therapy and tissue engineering from and toward the uterus. Semin Reprod Med. 2015b;33:366–72.PubMedCrossRefGoogle Scholar
  15. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials. 2011;32:3233–43.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Datta P, Ayan B, Ozbolat IT. Bioprinting for vascular and vascularized tissue biofabrication. Acta Biomater. 2017;51:1–20.PubMedCrossRefGoogle Scholar
  17. Ding L, Li X, Sun H, Su J, Lin N, Peault B, Song T, Yang J, Dai J, Hu Y. Transplantation of bone marrow mesenchymal stem cells on collagen scaffolds for the functional regeneration of injured rat uterus. Biomaterials. 2014;35:4888–900.PubMedCrossRefGoogle Scholar
  18. Ejzenberg D, Andraus W, Baratelli Carelli Mendes LR, Ducatti L, Song A, Tanigawa R, Rocha-Santos V, Macedo Arantes R, Soares JM Jr, Serafini PC, Bertocco De Paiva Haddad L, Pulcinelli Francisco R, Carneiro D’albuquerque LA, Chada Baracat E. Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility. Lancet. 2019;392(10165):2697–704.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Emmerson SJ, Gargett CE. Endometrial mesenchymal stem cells as a cell based therapy for pelvic organ prolapse. World J Stem Cells. 2016;8:202–15.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Feinberg AW. Engineered tissue grafts: opportunities and challenges in regenerative medicine. Wiley Interdiscip Rev Syst Biol Med. 2012;4:207–20.PubMedCrossRefGoogle Scholar
  21. Hellström M, El-Akouri RR, Sihlbom C, Olsson BM, Lengqvist J, Backdahl 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.PubMedCrossRefGoogle Scholar
  22. Hellström M, Moreno-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;106:487–496.e1.PubMedCrossRefGoogle Scholar
  23. Hellström M, Bandstein S, Brännström M. Uterine tissue engineering and the future of uterus transplantation. Ann Biomed Eng. 2017;45:1718–30.PubMedCrossRefGoogle Scholar
  24. 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 in a mouse model of decellularized uterine matrix transplantation. JCI Insight. 2016;1(8).Google Scholar
  25. House M, Sanchez CC, Rice WL, Socrate S, Kaplan DL. Cervical tissue engineering using silk scaffolds and human cervical cells. Tissue Eng Part A. 2010;16:2101–12.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Kim MR, Park DW, Lee JH, Choi DS, Hwang KJ, Ryu HS, Min CK. Progesterone-dependent release of transforming growth factor-beta1 from epithelial cells enhances the endometrial decidualization by turning on the Smad signalling in stromal cells. Mol Hum Reprod. 2005;11:801–8.PubMedCrossRefGoogle Scholar
  27. Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017;74:2345–60.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. Masuda H, Matsuzaki Y, Hiratsu E, Ono M, Nagashima T, Kajitani T, Arase T, Oda H, Uchida H, Asada H, Ito M, Yoshimura Y, Maruyama T, Okano H. Stem cell-like properties of the endometrial side population: implication in endometrial regeneration. PLoS One. 2010;5:e10387.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Meng CX, Andersson KL, Bentin-Ley U, Gemzell-Danielsson K, Lalitkumar PG. Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model. Fertil Steril. 2009;91:256–64.PubMedCrossRefGoogle Scholar
  31. Miki F, Maruyama T, Miyazaki K, Takao T, Yoshimasa Y, Katakura S, Hihara H, Uchida S, Masuda H, Uchida H, Nagai T, Shibata S, Tanaka M. The orientation of a decellularized uterine scaffold determines the tissue topology and architecture of the regenerated uterus in rats. Biol Reprod. 2019;100(5):1215–27. Scholar
  32. Miyazaki K, Maruyama T. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials. 2014;35:8791–800.PubMedCrossRefGoogle Scholar
  33. Olalekan SA, Burdette JE, Getsios S, Woodruff TK, Kim JJ. Development of a novel human recellularized endometrium that responds to a 28 day hormone treatment. Biol Reprod. 2017;96(5):971–81.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Ono M, Maruyama T, Masuda H, Kajitani T, Nagashima T, Arase T, Ito M, Ohta K, Uchida H, Asada H, Yoshimura Y, Okano H, Matsuzaki Y. Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proc Natl Acad Sci U S A. 2007;104:18700–5.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008;14:213–21.PubMedCrossRefGoogle Scholar
  36. Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, Kotton D, Vacanti JP. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med. 2010;16:927–33.PubMedCrossRefGoogle Scholar
  37. Padma AM, Tiemann TT, Alshaikh AB, Akouri R, Song MJ, Hellström M. Protocols for rat uterus isolation and decellularization: applications for uterus tissue engineering and 3D cell culturing. Methods Mol Biol. 2018;1577:161–75.PubMedCrossRefGoogle Scholar
  38. Park DW, Choi DS, Ryu HS, Kwon HC, Joo H, Min CK. A well-defined in vitro three-dimensional culture of human endometrium and its applicability to endometrial cancer invasion. Cancer Lett. 2003;195:185–92.PubMedCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason LE. Tissue-engineered lungs for in vivo implantation. Science. 2010;329:538–41.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Prakasam M, Locs J, Salma-Ancane K, Loca D, Largeteau A, Berzina-Cimdina L. Biodegradable materials and metallic implants-a review. J Funct Biomater. 2017;8.PubMedCentralCrossRefGoogle Scholar
  42. 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 regeneration in murine models. PLoS One. 2014;9:e103201.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Schutte SC, Taylor RN. A tissue-engineered human endometrial stroma that responds to cues for secretory differentiation, decidualization, and menstruation. Fertil Steril. 2012;97:997–1003.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Sengupta S, Sengupta J, Mittal S, Kumar S, Ghoshi D. Effect of human chorionic gonadotropin (hCG) on expression of vascular endothelial growth factor a (VEGF-a) in human mid-secretory endometrial cells in three-dimensional primary culture. Indian J Physiol Pharmacol. 2008;52:19–30.PubMedGoogle Scholar
  45. Shea LD, Woodruff TK, Shikanov A. Bioengineering the ovarian follicle microenvironment. Annu Rev Biomed Eng. 2014;16:29–52.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Simsa R, Padma AM, Heher P, HellstrÖM M, Jenndahl TA, Bergh NL, Fogelstrand P. Systematic in vitro comparison of decellularization protocols for blood vessels. PLoS One. 2018;13(12):e0209269.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med. 2013;19:646–51.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.PubMedCrossRefPubMedCentralGoogle Scholar
  49. Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, Zhang RR, Ueno Y, Zheng YW, Koike N, Aoyama S, Adachi Y, Taniguchi H. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499:481–4.PubMedCrossRefGoogle Scholar
  50. Testa G, Anthony T, McKenna GJ, Koon EC, Wallis K, Klintmalm GB, Reese JC, Johannesson L. Deceased donor uterus retrieval: a novel technique and workflow. Am J Transplant. 2018;18(3):679–83.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Ulrich D, Muralitharan R, Gargett CE. Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies. Expert Opin Biol Ther. 2013;13:1387–400.PubMedCrossRefGoogle Scholar
  52. Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, Milwid J, Kobayashi N, Tilles A, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med. 2010;16:814–20.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Vedadghavami A, Minooei F, Mohammadi MH, Khetani S, Rezaei Kolahchi A, Mashayekhan S, Sanati-Nezhad A. Manufacturing of hydrogel biomaterials with controlled mechanical properties for tissue engineering applications. Acta Biomater. 2017;62:42–63.PubMedCrossRefGoogle Scholar
  54. Wang HB, Lu SH, Lin QX, Feng LX, Li DX, Duan CM, Li YL, Wang CY. Reconstruction of endometrium in vitro via rabbit uterine endometrial cells expanded by sex steroid. Fertil Steril. 2010;93:2385–95.PubMedCrossRefGoogle Scholar
  55. Wong ML, Wong JL, Vapniarsky N, Griffiths LG. In vivo xenogeneic scaffold fate is determined by residual antigenicity and extracellular matrix preservation. Biomaterials. 2016;92:1–12.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Xiao S, Coppeta JR, Rogers HB, Isenberg BC, Zhu J, Olalekan SA, McKinnon KE, Dokic D, Rashedi AS, Haisenleder DJ, Malpani SS, Arnold-Murray CA, Chen K, Jiang M, Bai L, Nguyen CT, Zhang J, Laronda MM, Hope TJ, Maniar KP, Pavone ME, Avram MJ, Sefton EC, Getsios S, Burdette JE, Kim JJ, Borenstein JT, Woodruff TK. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat Commun. 2017;8:14584.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Young RC, Goloman G. Allo- and Xeno-reassembly of human and rat myometrium from cells and scaffolds. Tissue Eng Part A. 2013;19(19–20):2112–9.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Laboratory for Transplantation and Regenerative MedicineInstitute of Clinical Science, Sahlgrenska Academy, University of GothenburgGothenburgSweden
  2. 2.Department of Obstetrics and GynecologyInstitute of Clinical Science, Sahlgrenska Academy, University of GothenburgGothenburgSweden
  3. 3.Department of Obstetrics and GynecologySahlgrenska Academy, University of Gothenburg, Sahlgrenska University HospitalGothenburgSweden
  4. 4.Stockholm IVF-EUGINStockholmSweden

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