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The Bioengineered Uterus: A Possible Future

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Book cover Uterus Transplantation

Abstract

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.

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Abbreviations

3D:

Three-dimensional

ECM:

Extracellular matrix

ES:

Embryonic stem (cells)

GFP:

Green fluorescent protein

HHP:

High hydrostatic pressure

iPS:

Induced pluripotent stem (cells)

MSCs:

Mesenchymal stem cells

SDS:

Sodium dodecyl sulfate

STAT3:

Signal transducer and activator of transcription 3

UTx:

Uterus transplantation

References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367:1241–6.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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;18

    Article  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials. 2011;32:3233–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Datta P, Ayan B, Ozbolat IT. Bioprinting for vascular and vascularized tissue biofabrication. Acta Biomater. 2017;51:1–20.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Feinberg AW. Engineered tissue grafts: opportunities and challenges in regenerative medicine. Wiley Interdiscip Rev Syst Biol Med. 2012;4:207–20.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hellström M, Bandstein S, Brännström M. Uterine tissue engineering and the future of uterus transplantation. Ann Biomed Eng. 2017;45:1718–30.

    Article  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017;74:2345–60.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1093/biolre/ioz004.

    Article  PubMed  Google Scholar 

  • Miyazaki K, Maruyama T. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials. 2014;35:8791–800.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Shea LD, Woodruff TK, Shikanov A. Bioengineering the ovarian follicle microenvironment. Annu Rev Biomed Eng. 2014;16:29–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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).

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Hellström, M., Brännström, M. (2020). The Bioengineered Uterus: A Possible Future. In: Brännström, M. (eds) Uterus Transplantation. Springer, Cham. https://doi.org/10.1007/978-3-319-94162-2_29

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