{"paper_id":"372a1f60-5c82-405d-8b7c-2702f1db6832","body_text":"Abstract\nEndometriosis is a chronic condition where tissue similar to the endometrium grows outside\nthe uterus, affecting 5-10% of women and causing pelvic pain, painful periods, and infertility.\nDiseases of the endometrium, the lining of the uterus, can lead to a variety of reproductive health\nissues, including infertility, irregular bleeding, and endometrial cancer. Researchers have developed\nadvanced in vitro systems using uterine organoids and decellularized tissue scaffolds to understand\nand model these diseases. The main limitations of traditional 2D monolayer cultures include reduced\nbiological activity, reduced hormone responsiveness, and lack of interaction with ECM. Researchers\nhave investigated 3D culture approaches to address these shortcomings, such as scaffold-free organoids\nand decellularized tissue scaffolds. Organoid systems can better recapitulate the cellular heterogeneity\nand physiological functions of the native endometrium. Decellularization protocols have been\noptimized to generate intact uterine scaffolds that preserve the structural and compositional features\nof the ECM. Implantation of these bioscaffolds into animal models demonstrated their biocompatibility\nand regenerative potential. Further refinements of organoid and scaffold technologies, including\nchemically defined matrices and organ-on-a-chip platforms, will improve our ability to model the\nuterus. Integration of these advanced in vitro models with patient-derived cells will enable personalized\ndisease modeling and the development of targeted therapies. The combination of organoids,\ndecellularized scaffolds, and microfluidic technologies holds great potential for exploring reproductive\nbiology, drug screening, and developing regenerative therapies for uterine diseases and infertility.\nKeywords: Endometriosis, organoid, uterus, tissue engineering, cell culture, ondometer.\n[1]\nParasar, P.; Ozcan, P.; Terry, K.L. Endometriosis: Epidemiology, diagnosis and clinical management. Curr. Obstet. Gynecol. Rep., 2017, 6(1), 34-41.\n[http://dx.doi.org/10.1007/s13669-017-0187-1] [PMID: 29276652]\n[http://dx.doi.org/10.1007/s13669-017-0187-1] [PMID: 29276652]\n[2]\nWu, J.; Lin, S.; Kong, S. Psychological stress and functional endometrial disorders: Update of mechanism insights. Front. Endocrinol. (Lausanne), 2021, 12, 690255.\n[http://dx.doi.org/10.3389/fendo.2021.690255] [PMID: 34413829]\n[http://dx.doi.org/10.3389/fendo.2021.690255] [PMID: 34413829]\n[3]\nNijkang, N.P.; Anderson, L.; Markham, R.; Manconi, F. Endometrial polyps: Pathogenesis, sequelae and treatment. SAGE Open Med., 2019, 7, 2050312119848247.\n[http://dx.doi.org/10.1177/2050312119848247] [PMID: 31105939]\n[http://dx.doi.org/10.1177/2050312119848247] [PMID: 31105939]\n[4]\nRing, K.L.; Mills, A.M.; Modesitt, S.C. Endometrial hyperplasia. Obstet. Gynecol., 2022, 140(6), 1061-1075.\n[PMID: 36357974]\n[PMID: 36357974]\n[5]\nEndometrial hyperplasia Seminars in Diagnostic Pathology; Mills, A.M.; Longacre, T.A., Eds.; Elsevier, 2010.\n[6]\nMorice, P.; Leary, A.; Creutzberg, C.; Abu-Rustum, N.; Darai, E. Endometrial cancer. Lancet, 2016, 387(10023), 1094-1108.\n[http://dx.doi.org/10.1016/S0140-6736(15)00130-0] [PMID: 26354523]\n[http://dx.doi.org/10.1016/S0140-6736(15)00130-0] [PMID: 26354523]\n[7]\nIkhena, D.E.; Bulun, S.E. Literature review on the role of uterine fibroids in endometrial function. Reprod. Sci., 2018, 25(5), 635-643.\n[http://dx.doi.org/10.1177/1933719117725827] [PMID: 28826369]\n[http://dx.doi.org/10.1177/1933719117725827] [PMID: 28826369]\n[8]\nSommers, S.C. Defining the pathology of endometrial hyperplasia, dysplasia and carcinoma. Pathol. Res. Pract., 1982, 174(3), 175-197.\n[http://dx.doi.org/10.1016/S0344-0338(82)80066-6] [PMID: 6292884]\n[http://dx.doi.org/10.1016/S0344-0338(82)80066-6] [PMID: 6292884]\n[9]\nStringfellow, H.F.; Elliot, V.J. Endometrial metaplasia. Diagn. Histopathol., 2017, 23(7), 303-310.\n[http://dx.doi.org/10.1016/j.mpdhp.2017.05.006]\n[http://dx.doi.org/10.1016/j.mpdhp.2017.05.006]\n[10]\nRafique, S.; Decherney, A.H. Medical management of endometriosis. Clin. Obstet. Gynecol., 2017, 60(3), 485-496.\n[http://dx.doi.org/10.1097/GRF.0000000000000292] [PMID: 28590310]\n[http://dx.doi.org/10.1097/GRF.0000000000000292] [PMID: 28590310]\n[11]\nFilby, C.E.; Wyatt, K.A.; Mortlock, S. Comparison of organoids from menstrual fluid and hormone-treated endometrium: Novel tools for gynecological research. J. Pers. Med., 2021, 11(12), 1314.\n[http://dx.doi.org/10.3390/jpm11121314] [PMID: 34945786]\n[http://dx.doi.org/10.3390/jpm11121314] [PMID: 34945786]\n[12]\nKovina, M.V.; Krasheninnikov, M.E.; Dyuzheva, T.G. Human endometrial stem cells: High-yield isolation and characterization. Cytotherapy, 2018, 20(3), 361-374.\n[http://dx.doi.org/10.1016/j.jcyt.2017.12.012] [PMID: 29397307]\n[http://dx.doi.org/10.1016/j.jcyt.2017.12.012] [PMID: 29397307]\n[13]\nWang, F.; Qualls, A.E.; Marques-Fernandez, L.; Colucci, F. Biology and pathology of the uterine microenvironment and its natural killer cells. Cell. Mol. Immunol., 2021, 18(9), 2101-2113.\n[http://dx.doi.org/10.1038/s41423-021-00739-z] [PMID: 34426671]\n[http://dx.doi.org/10.1038/s41423-021-00739-z] [PMID: 34426671]\n[14]\nCousins, F.L.; Pandoy, R.; Jin, S.; Gargett, C.E. The elusive endometrial epithelial stem/progenitor cells. Front. Cell Dev. Biol., 2021, 9, 640319.\n[http://dx.doi.org/10.3389/fcell.2021.640319] [PMID: 33898428]\n[http://dx.doi.org/10.3389/fcell.2021.640319] [PMID: 33898428]\n[15]\nLiu, M.; Ji, M.; Cheng, J. Deciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution. Nat. Commun., 2023, 14(1), 7356.\n[http://dx.doi.org/10.1038/s41467-023-43102-8] [PMID: 37963860]\n[http://dx.doi.org/10.1038/s41467-023-43102-8] [PMID: 37963860]\n[16]\nArnold, J.T.; Kaufman, D.G.; Seppälä, M.; Lessey, B.A. Endometrial stromal cells regulate epithelial cell growth in vitro: a new co-culture model. Hum. Reprod., 2001, 16(5), 836-845.\n[http://dx.doi.org/10.1093/humrep/16.5.836] [PMID: 11331626]\n[http://dx.doi.org/10.1093/humrep/16.5.836] [PMID: 11331626]\n[17]\nGargett, C.E. Uterine stem cells: What is the evidence? Hum. Reprod. Update, 2007, 13(1), 87-101.\n[http://dx.doi.org/10.1093/humupd/dml045] [PMID: 16960017]\n[http://dx.doi.org/10.1093/humupd/dml045] [PMID: 16960017]\n[18]\nSchutte, S.C.; Taylor, R.N. A tissue-engineered human endometrial stroma that responds to cues for secretory differentiation, decidualization, and menstruation. Fertil. Steril., 2012, 97(4), 997-1003.\n[http://dx.doi.org/10.1016/j.fertnstert.2012.01.098] [PMID: 22306710]\n[http://dx.doi.org/10.1016/j.fertnstert.2012.01.098] [PMID: 22306710]\n[19]\nShved, N.; Egorova, A.; Osinovskaya, N.; Kiselev, A. Development of primary monolayer cell model and organotypic model of uterine leiomyoma. Methods Protoc., 2022, 5(1), 16.\n[http://dx.doi.org/10.3390/mps5010016] [PMID: 35200532]\n[http://dx.doi.org/10.3390/mps5010016] [PMID: 35200532]\n[20]\nChitcholtan, K.; Asselin, E.; Parent, S.; Sykes, P.H.; Evans, J.J. Differences in growth properties of endometrial cancer in three dimensional (3D) culture and 2D cell monolayer. Exp. Cell Res., 2013, 319(1), 75-87.\n[http://dx.doi.org/10.1016/j.yexcr.2012.09.012] [PMID: 23022396]\n[http://dx.doi.org/10.1016/j.yexcr.2012.09.012] [PMID: 23022396]\n[21]\nXu, J.; Zhang, L.; Ye, Z. A 3D “sandwich” co-culture system with vascular niche supports mouse embryo development from E3.5 to E7.5 in vitro. Stem Cell Res. Ther., 2023, 14(1), 349.\n[http://dx.doi.org/10.1186/s13287-023-03583-2] [PMID: 38072932]\n[http://dx.doi.org/10.1186/s13287-023-03583-2] [PMID: 38072932]\n[22]\nCheng, Y.H.; Huang, C.W.; Lien, H.T. A preliminary investigation of the roles of endometrial cells in endometriosis development via in vitro and in vivo analyses. Int. J. Mol. Sci., 2024, 25(7), 3873.\n[http://dx.doi.org/10.3390/ijms25073873] [PMID: 38612685]\n[http://dx.doi.org/10.3390/ijms25073873] [PMID: 38612685]\n[23]\nMuruganandan, S.; Fan, X.; Dhal, S.; Nayak, N.R. Development of a 3D tissue slice culture model for the study of human endometrial repair and regeneration. Biomolecules, 2020, 10(1), 136.\n[http://dx.doi.org/10.3390/biom10010136] [PMID: 31947662]\n[http://dx.doi.org/10.3390/biom10010136] [PMID: 31947662]\n[24]\nHellström, M.; El-Akouri, R.R.; Sihlbom, C. Towards the development of a bioengineered uterus: Comparison of different protocols for rat uterus decellularization. Acta Biomater., 2014, 10(12), 5034-5042.\n[http://dx.doi.org/10.1016/j.actbio.2014.08.018] [PMID: 25169258]\n[http://dx.doi.org/10.1016/j.actbio.2014.08.018] [PMID: 25169258]\n[25]\nSehic, E.; de Miguel Gómez, L.; Rabe, H. Transplantation of a bioengineered tissue patch promotes uterine repair in the sheep. Biomater. Sci., 2024, 12(8), 2136-2148.\n[http://dx.doi.org/10.1039/D3BM01912H] [PMID: 38482883]\n[http://dx.doi.org/10.1039/D3BM01912H] [PMID: 38482883]\n[26]\nDaryabari, S.S.; Fendereski, K.; Ghorbani, F. Whole-organ decellularization of the human uterus and in vivo application of the bio-scaffolds in animal models. J. Assist. Reprod. Genet., 2022, 39(6), 1237-1247.\n[http://dx.doi.org/10.1007/s10815-022-02492-2] [PMID: 35513746]\n[http://dx.doi.org/10.1007/s10815-022-02492-2] [PMID: 35513746]\n[27]\nWiwatpanit, T.; Murphy, A.R.; Lu, Z. Scaffold-free endometrial organoids respond to excess androgens associated with polycystic ovarian syndrome. J. Clin. Endocrinol. Metab., 2020, 105(3), 769-780.\n[http://dx.doi.org/10.1210/clinem/dgz100] [PMID: 31614364]\n[http://dx.doi.org/10.1210/clinem/dgz100] [PMID: 31614364]\n[28]\nLi, W-X.; Liang, G-T.; Yan, W. Artificial uterus on a microfluidic chip. Chin. J. Anal. Chem., 2013, 41(4), 467-472.\n[http://dx.doi.org/10.1016/S1872-2040(13)60639-8]\n[http://dx.doi.org/10.1016/S1872-2040(13)60639-8]\n[29]\nXiao, S.; Coppeta, J.R.; Rogers, H.B. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat. Commun., 2017, 8(1), 14584.\n[http://dx.doi.org/10.1038/ncomms14584] [PMID: 28350383]\n[http://dx.doi.org/10.1038/ncomms14584] [PMID: 28350383]\n[30]\nYoung, R.E.; Huh, D.D. Organ-on-a-chip technology for the study of the female reproductive system. Adv. Drug Deliv. Rev., 2021, 173, 461-478.\n[http://dx.doi.org/10.1016/j.addr.2021.03.010] [PMID: 33831478]\n[http://dx.doi.org/10.1016/j.addr.2021.03.010] [PMID: 33831478]\n[31]\nLi, Y.; Tang, P.; Cai, S.; Peng, J.; Hua, G. Organoid based personalized medicine: from bench to bedside. Cell Regen. (Lond.), 2020, 9(1), 21.\n[http://dx.doi.org/10.1186/s13619-020-00059-z] [PMID: 33135109]\n[http://dx.doi.org/10.1186/s13619-020-00059-z] [PMID: 33135109]\n[32]\nHeidari-Khoei, H.; Esfandiari, F.; Hajari, M.A.; Ghorbaninejad, Z.; Piryaei, A.; Baharvand, H. Organoid technology in female reproductive biomedicine. Reprod. Biol. Endocrinol., 2020, 18(1), 64.\n[http://dx.doi.org/10.1186/s12958-020-00621-z] [PMID: 32552764]\n[http://dx.doi.org/10.1186/s12958-020-00621-z] [PMID: 32552764]\n[33]\nArjmand, B.; Rabbani, Z.; Soveyzi, F. Advancement of organoid technology in regenerative medicine. Regen. Eng. Transl. Med., 2023, 9(1), 83-96.\n[http://dx.doi.org/10.1007/s40883-022-00271-0] [PMID: 35968268]\n[http://dx.doi.org/10.1007/s40883-022-00271-0] [PMID: 35968268]\n[34]\nYang, S.; Hu, H.; Kung, H. Organoids: The current status and biomedical applications. MedComm, 2023, 4(3), e274.\n[http://dx.doi.org/10.1002/mco2.274] [PMID: 37215622]\n[http://dx.doi.org/10.1002/mco2.274] [PMID: 37215622]\n[35]\nAlzamil, L.; Nikolakopoulou, K.; Turco, M.Y. Organoid systems to study the human female reproductive tract and pregnancy. Cell Death Differ., 2021, 28(1), 35-51.\n[http://dx.doi.org/10.1038/s41418-020-0565-5] [PMID: 32494027]\n[http://dx.doi.org/10.1038/s41418-020-0565-5] [PMID: 32494027]\n[36]\nRawlings, T.M.; Makwana, K.; Tryfonos, M.; Lucas, E.S. Organoids to model the endometrium: Implantation and beyond. Reprod. Fertility, 2021, 2(3), R85-R101.\n[http://dx.doi.org/10.1530/RAF-21-0023] [PMID: 35118399]\n[http://dx.doi.org/10.1530/RAF-21-0023] [PMID: 35118399]\n[37]\nChumduri, C.; Turco, M.Y. Organoids of the female reproductive tract. J. Mol. Med. (Berl.), 2021, 99(4), 531-553.\n[http://dx.doi.org/10.1007/s00109-020-02028-0] [PMID: 33580825]\n[http://dx.doi.org/10.1007/s00109-020-02028-0] [PMID: 33580825]\n[38]\nGu, Z.Y.; Jia, S.Z.; Liu, S.; Leng, J.H. Endometrial organoids: A new model for the research of endometrial-related diseases. Biol. Reprod., 2020, 103(5), 918-926.\n[http://dx.doi.org/10.1093/biolre/ioaa124] [PMID: 32697306]\n[http://dx.doi.org/10.1093/biolre/ioaa124] [PMID: 32697306]\n37\n1","source_license":"CC0","license_restricted":false}