Mesenchymal stem cells to treat female infertility; future perspective and challenges: A review
Infertility negatively impacts the overall health and social life of affected individuals and couples. Female infertility is their inability to perceive pregnancy. To date, polycystic ovary syndrome, primary ovarian insufficiency, fallopian tube obstruction, endometriosis, and intrauterine synechiae have been identified
as the primary causes of infertility in women. However, despite the mutual efforts of clinicians and research scientists, the development of an effective treatment modality has met little success in combating female infertility. Intriguingly, significant research has demonstrated mesenchymal stem cells as an optimal source for treating infertility disorders. Therefore, here we attempted to capsulize to date available studies to summarize the therapeutic potential of mesenchymal stem cells in combating infertility in women by focusing on the underlying mechanism through which stem cells can reduce the effects of ovarian disorders. Furthermore, we also discussed the preclinical and clinical application of stem cell therapy, their limitation, and the future perspective to minimize these limitations.
Key words: Pregnancy, Infertility, Female, Stem cell transplantation, Uterine diseases, Mesenchymal stem cells.
 Wang J, Liu Ch, Fujino M, Tong G, Zhang Q, Li XK, et al. Stem cells as a resource for treatment of infertility-related diseases. Curr Mol Med 2019; 19: 519–546
 Mehra BL, Skandhan KP, Prasad BS, Pawankumar G, Singh G, Jaya V. Male infertility rate: A retrospective study. Urologia 2018; 85: 22–24.
 Hansen KR, He AL, Styer AK, Wild RA, Butts S, Engmann L, et al. Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulationintrauterine insemination. Fertil Steril 2016; 105: 1575–1583.
 Gurunath S, Pandian Z, Anderson RA, Bhattacharya S. Defining infertility: A systematic review of prevalence studies. Hum Reprod Update 2011; 17: 575–588.
 Bushnik T, Cook JL, Yuzpe AA, Tough S, Collins J. Estimating the prevalence of infertility in Canada. Hum Reprod 2012; 27: 738–746.
 Deroux A, Dumestre-Perard Ch, Dunand-Faure C, Bouillet L, Hoffmann P. Female infertility and serum auto-antibodies: A systematic review. Clin Rev Allergy Immunol 2017; 53: 78–86.
 Zhao Y-X, Chen Sh-R, Su P-P, Huang F-H, Shi Y-Ch, Shi Q-Y, et al. Using mesenchymal stem cells to treat female infertility: An update on female reproductive diseases. Stem Cells Int 2019; 2019: 9071720.
 Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA,Hinton RA, et al. Population study of causes, treatment, and outcome of infertility. Br Med J 1985; 291: 1693–1697.
 Esfandyari S, Chugh RM, Park H-S, Hobeika E, Ulin M, Al-Hendy A. Mesenchymal stem cells as a bio organ for treatment of female infertility. Cells 2020; 9: 2253.
 Gunn DD, Bates GW. Evidence-based approach to unexplained infertility: A systematic review. Fertil Steril 2016; 105: 1566–1574.
 Ohannessian A, Loundou A, Gnisci A, PaulmyerLacroix O, Perrin J, Courbiere B. Unexplained infertility: Live-birth’s prognostic factors to determine the ART management. Minerva Ginecol 2017; 69: 526–532.
 Cissen M, Bensdorp A, Cohlen BJ, Repping S, de Bruin JP, van Wely M. Assisted reproductive technologies for male subfertility. Cochrane Database Syst Rev 2016; 2: CD000360.
 Inhorn MC, Patrizio P. Infertility around the globe: New thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update 2015; 21: 411–426.
 Rungsiwiwut R, Virutamasen P, Pruksananonda K. Mesenchymal stem cells for restoring endometrial function: An infertility perspective. Reprod Med Biol 2021; 20: 13–19.
 Blum B, Benvenisty N. The tumorigenicity of human embryonic stem cells. Adv Cancer Res 2008; 100: 133– 158.
 Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: A systematic analysis of 277 health surveys. PLoS Med 2012; 9: e1001356.
 May-Panloup P, Boucret L, Chao de la Barca JM, Desquiret-Dumas V, Ferré-L’Hotellier V, Morinière C, et al. Ovarian ageing: The role of mitochondria in oocytes and follicles. Hum Reprod Update 2016; 22: 725–743.
 Al-Inany H. Female infertility. Clin Evid 2006; 15: 2465– 2487.
 Jobling Ph, O’Hara K, Hua S. Female reproductive tract pain: Targets, challenges, and outcomes. Front Pharmacol 2014; 5: 17.
 Mourad S, Brown J, Farquhar C. Interventions for the prevention of OHSS in ART cycles: An overview of Cochrane reviews. Cochrane Database Syst Rev 2017; 1: CD012103.
 Scaparrotta A, Chiarelli F, Verrotti A. Potential teratogenic effects of clomiphene citrate. Drug Saf 2017; 40: 761– 769.
 Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008; 100: 475–482.
 Vermeulen RFM, Korse CM, Kenter GG, Broodvan Zanten MMA, Beurden MV. Safety of hormone replacement therapy following risk-reducing salpingooophorectomy: Systematic review of literature and guidelines. Climacteric 2019; 22: 352–360.
 Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: An analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update 2016; 22: 687–708.
 Hayashi K, Hikabe O, Obata Y, Hirao Y. Reconstitution of mouse oogenesis in a dish from pluripotent stem cells. Nat Protoc 2017; 12: 1733–1744.
 Javidpou M, Seifati SM, Farashahi-Yazd E, HajizadehTafti F, Golzadeh J, Akyash F, et al. Mesenchymal stem/stromal-like cells from diploid and triploid human embryonic stem cells display different gene expression profiles. Iran Biomed J 2021; 25: 99–105.
 Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: Multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med 2017; 6: 2173–2185.
 Shah JS, Sabouni R, Cayton Vaught KC, Owen CM, Albertini DF, Segars JH. Biomechanics and mechanical signaling in the ovary: A systematic review. J Assist Reprod Genet 2018; 35: 1135–1148.
 Gupta PK, Krishna M, Chullikana A, Desai S, Murugesan R, Dutta S, et al. Administration of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells in critical limb ischemia due to Buerger’s disease: Phase II study report suggests clinical efficacy. Stem Cells Transl Med 2017; 6: 689– 699.
 Malard PF, Peixer MAS, Grazia JG, Brunel HDSS, Feres LF, Villarroel CL, et al. Intraovarian injection of mesenchymal stem cells improves oocyte yield and in vitro embryo production in a bovine model of fertility loss. Sci Rep 2020; 10: 8018.
 Ball LM, Bernardo ME, Roelofs H, van Tol MJ, Contoli B, Zwaginga JJ, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versushost disease. Br J Haematol 2013; 163: 501–509.
 Ciccocioppo R, Gallia A, Sgarella A, Kruzliak P, Gobbi PG, Corazza GR. Long-term follow-up of Crohn disease fistulas after local injections of bone marrow-derived mesenchymal stem cells. Mayo Clin Proc 2015; 90: 747– 755.
 Kim TH, Choi JH, Jun Y, Lim SM, Park S, Paek JY, et al. 3D-cultured human placenta-derived mesenchymal stem cell spheroids enhance ovary function by inducing folliculogenesis. Sci Rep 2018; 8: 15313.
 Huang B, Lu J, Ding C, Zou Q, Wang W, Li H. Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD. Stem Cell Res Ther 2018; 9: 216.
 Xie Q, Xiong X, Xiao N, He K, Chen M, Peng J, et al. Mesenchymal stem cells alleviate DHEAinduced polycystic ovary syndrome (PCOS) by inhibiting inflammation in mice. Stem Cells Int 2019; 2019: 9782373.
 Li J, Yu Q, Huang H, Deng W, Cao X, Adu-Frimpong M, et al. Human chorionic plate-derived mesenchymal stem cells transplantation restores ovarian function in a chemotherapy-induced mouse model of premature ovarian failure. Stem Cell Res Ther 2018; 9: 81.
 Yoon SY, Yoon JA, Park M, Shin EY, Jung S, Lee JE, et al. Recovery of ovarian function by human embryonic stem cell-derived mesenchymal stem cells in cisplatin-induced premature ovarian failure in mice. Stem Cell Res Ther 2020; 11: 255.
 Caplan AI. Why are MSCs therapeutic? New data: New insight. J Pathol 2009; 217: 318–324.
 de Oliveira Bravo M, Carvalho JL, Saldanha-Araujo F. Adenosine production: A common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression. Purinergic Signal 2016; 12: 595– 609.
 Haddad R, Saldanha-Araujo F. Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: What do we know so far? Biomed Res Int 2014; 2014: 216806.
 Chang L-B, Peng S-Y, Chou C-J, Chen Y-J, Shiu J-S, Tu P-A, et al. Therapeutic potential of amniotic fluid stem cells to treat bilateral ovarian dystrophy in dairy cows in a subtropical region. Reprod Domest Anim 2018; 53: 433– 441.
 Grady ST, Watts AE, Thompson JA, Penedo MCT, Konganti K, Hinrichs K. Effect of intra-ovarian injection of mesenchymal stem cells in aged mares. J Assist Reprod Genet 2019; 36: 543–556.
 Fu YX, Ji J, Shan F, Li J, Hu R. Human mesenchymal stem cell treatment of premature ovarian failure: New challenges and opportunities. Stem Cell Res Ther 2021; 12: 161.
 Mirzaeian L, Eftekhari-Yazdi P, Esfandiari F, Eivazkhani F, Rezazadeh Valojerdi M, Moini A, et al. Induction of mouse peritoneum mesenchymal stem cells into germ cell-like cells using follicular fluid and cumulus cells-conditioned media. Stem Cells Dev 2019; 28: 554–564.
 Kalhori Z, Azadbakht M, Soleimani Mehranjani M, Shariatzadeh MA. Improvement of the folliculogenesis by transplantation of bone marrow mesenchymal stromal cells in mice with induced polycystic ovary syndrome. Cytotherapy 2018; 20: 1445–1458.
 Jafarzadeh H, Nazarian H, Ghaffari Novin M, Shams Mofarahe Z, Eini F, Piryaei A. Improvement of oocyt in vitro maturation from mice with polycystic ovary syndrome by human mesenchymal stromal cellconditioned media. J Cell Biochem 2018; 119: 10365– 10375.
 Chugh RM, Park HS, El Andaloussi A, Elsharoud A, Esfandyari S, Ulin M, et al. Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10. Stem Cell Res Ther 2021; 12: 388.
 Nagamura-Inoue T, He H. Umbilical cord-derived mesenchymal stem cells: Their advantages and potential clinical utility. World J Stem Cells 2014; 6: 195–202.
 Mohamed SA, Shalaby S, Brakta S, Elam L, Elsharoud A, Al-Hendy A. Umbilical cord blood mesenchymal stem cells as an infertility treatment for chemotherapy induced premature ovarian insufficiency. Biomedicines 2019; 7: 7.
 Song D, Zhong Y, Qian C, Zou Q, Ou J, Shi Y, et al. Human umbilical cord mesenchymal stem cells therapy in cyclophosphamide-induced premature ovarian failure rat model. Biomed Res Int 2016; 2016: 2517514.
 Zhu SF, Hu HB, Xu HY, Fu XF, Peng DX, Su WY, et al. Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries. J Cell Mol Med 2015; 19: 2108–2117.
 Wang Sh, Yu L, Sun M, Mu S, Wang C, Wang D, et al. The therapeutic potential of umbilical cord mesenchymal stem cells in mice premature ovarian failure. Biomed Res Int 2013; 2013: 690491.
 Zhang Ch. The roles of different stem cells in premature ovarian failure. Curr Stem Cell Res Ther 2020; 15: 473– 481.
 Li J, Mao QX, He JJ, She HQ, Zhang Zh, Yin ChY. Human umbilical cord mesenchymal stem cells improve the reserve function of perimenopausal ovary via a paracrine mechanism. Stem Cell Res Ther 2017; 8: 55.
 Zhang L, Li Y, Guan CY, Tian S, Lv XD, Li JH, et al. Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase. Stem Cell Res Ther 2018; 9: 36.
 Elfayomy AK, Almasry SM, El-Tarhouny SA, Eldomiaty MA. Human umbilical cord blood-mesenchymal stem cells transplantation renovates the ovarian surface epithelium in a rat model of premature ovarian failure: Possible direct and indirect effects. Tissue Cell 2016; 48: 370–382.
 Yang X, Zhang M, Zhang Y, Li W, Yang B. Mesenchymal stem cells derived from wharton jelly of the human umbilical cord ameliorate damage to human endometrial stromal cells. Fertil Steril 2011; 96: 1029–1036.
 Cao Y, Sun H, Zhu H, Zhu X, Tang X, Yan G, et al. Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: A phase I clinical trial. Stem Cell Res Ther 2018; 9: 192.
 Tian Ch, He J, An Y, Yang Z, Yan D, Pan H, et al. Bone marrow mesenchymal stem cells derived from juvenile macaques reversed ovarian ageing in elderly macaques. Stem Cell Res Ther 2021; 12: 460.
 Besikcioglu HE, Saribas GS, Ozogul C, Tiryaki M, Kilic S, Pinarli FA, et al. Determination of the effects of bone marrow derived mesenchymal stem cells and ovarian stromal stem cells on follicular maturation in cyclophosphamide induced ovarian failure in rats. Taiwan J Obstet Gynecol 2019; 58: 53–59.
 Xu Sh, Chan RWS, Ng EHY, Yeung WSB. Spatial and temporal characterization of endometrial mesenchymal stem-like cells activity during the menstrual cycle. Exp Cell Res 2017; 350: 184–189.
 Meng X, Ichim TE, Zhong J, Rogers A, Yin Z, Jackson J, et al. Endometrial regenerative cells: A novel stem cell population. J Transl Med 2007; 5: 57.
 Zhong Zh, Patel AN, Ichim TE, Riordan NH, Wang H, Min WP, et al. Feasibility investigation of allogeneic endometrial regenerative cells. J Transl Med 2009; 7: 15.
 Zhang S, Li P, Yuan Z, Tan J. Platelet-rich plasma improves therapeutic effects of menstrual blood-derived stromal cells in rat model of intrauterine adhesion. Stem Cell Res Ther 2019; 10: 61.
 Zheng Sh-X, Wang J, Wang X-L, Ali A, Wu L-M, Liu YSh. Feasibility analysis of treating severe intrauterine adhesions by transplanting menstrual blood-derived stem cells. Int J Mol Med 2018; 41: 2201–2212.
 Tan J, Li P, Wang Q, Li Y, Li X, Zhao D, et al. Autologous menstrual blood-derived stromal cells transplantation for severe Asherman’s syndrome. Hum Reprod 2016; 31: 2723–2729.
 Akyash F, Javidpou M, Farashahi Yazd E, Golzadeh J, Hajizadeh-Tafti F, Aflatoonian R, et al. Characteristics of the human endometrial regeneration cells as a potential source for future stem cell-based therapies: A lab resources study. Int J Reprod BioMed 2020; 18: 943– 950.
 Domnina A, Novikova P, Obidina J, Fridlyanskaya I, Alekseenko L, Kozhukharova I, et al. Human mesenchymal stem cells in spheroids improve fertility in model animals with damaged endometrium. Stem Cell Res Ther 2018; 9: 50.
 Hu J, Song K, Zhang J, Zhang Y, Tan BZh. Effects of menstrual bloodderived stem cells on endometrial injury repair. Mol Med Rep 2019; 19: 813–820.
 Zhu H, Jiang Y, Pan Y, Shi L, Zhang S. Human menstrual blood-derived stem cells promote the repair of impaired endometrial stromal cells by activating the p38 MAPK and AKT signaling pathways. Reprod Biol 2018; 18: 274– 281.
 Yan Zh, Guo F, Yuan Q, Shao Y, Zhang Y, Wang H, et al. Endometrial mesenchymal stem cells isolated from menstrual blood repaired epirubicin-induced damage to human ovarian granulosa cells by inhibiting the expression of Gadd45b in cell cycle pathway. Stem Cell Res Ther 2019; 10: 4.
 Wang Zh, Wang Y, Yang T, Li J, Yang X. Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice. Stem Cell Res Ther 2017; 8: 49.
 Cherqui S, Kingdon KM, Thorpe C, Kurian SM, Salomon DR. Lentiviral gene delivery of vMIP-II to transplanted endothelial cells and endothelial progenitors is proangiogenic in vivo. Mol Ther 2007; 15: 1264–1272.
 Huang J, Zhang Z, Guo J, Ni A, Deb A, Zhang L, et al. Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ Res 2010; 106: 1753–1762.
 Bhang SH, Lee S, Shin JY, Lee TJ, Jang HK, Kim BS. Efficacious and clinically relevant conditioned medium of human adipose-derived stem cells for therapeutic angiogenesis. Mol Ther 2014; 22: 862–872.
 Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med 2014; 92: 387– 397.
 Adib M, Seifati SM, Ashkezari MD, Khoradmehr A, Rezaee-Ranjbar-Sardari R, Tahajjodi, et al. The effect of the human cumulus cells-conditioned medium on in vitro maturation of mouse oocyte: An experimental study. Int J Reprod BioMed 2020; 18: 1019–1028.
 Adib M, Seifati SM, Dehghani Ashkezari M, Akyash F, Khoradmehr A, Aflatoonian B. Effect of human testicular cells conditioned medium on in vitro maturation and morphology of mouse oocytes. Int J Fertil Steril 2020; 14: 175–184.
 Lacham-Kaplan O, Chy H, Trounson A. Testicular cell conditioned medium supports differentiation of embryonic stem cells into ovarian structures containing oocytes. Stem Cells 2006; 24: 266–273.
 Shah SM, Saini N, Singh MK, Manik R, Singla SK, Palta P, et al. Testicular cell-conditioned medium supports embryonic stem cell differentiation toward germ lineage and to spermatocyte-and oocyte-like cells. Theriogenology 2016; 86: 715–729.
 Sutton-McDowall ML, Mottershead DG, Gardner DK, Gilchrist RB, Thompson JG. Metabolic differences in bovine cumulus-oocyte complexes matured in vitro in the presence or absence of folliclestimulating hormone and bone morphogenetic protein 15. Biol Reprod 2012; 87: 87.
 Lou G, Chen Zh, Zheng M, Liu Y. Mesenchymal stem cellderived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med 2017; 49: e346.
 Zhang H, Lyden D. Asymmetric-flow field-flow fractionation technology for exomere and small extracellular vesicle separation and characterization. Nat Protoc 2019; 14: 1027–1053.
 Xiong ZH, Wei J, Lu MQ, Jin MY, Geng HL. Protective effect of human umbilical cord mesenchymal stem cell exosomes on preserving the morphology and angiogenesis of placenta in rats with preeclampsia. Biomed Pharmacother 2018; 105: 1240–1247.
 Zhang Q, Sun J, Huang Y, Bu Sh, Guo Y, Gu T, et al. Human amniotic epithelial cell-derived exosomes restore ovarian function by transferring MicroRNAs against apoptosis. Mol Ther Nucleic Acids 2019; 16: 407– 418.
 Xiao GY, Cheng Ch-Ch, Chiang Y-Sh, Cheng WT-K, Liu I-H, Wu Sh-Ch. Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy. Sci Rep 2016; 6: 23120.
 Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells 2015; 33: 2158–2168.
 Na J, Kim GJ. Recent trends in stem cell therapy for premature ovarian insufficiency and its therapeutic potential: A review. J Ovarian Res 2020; 13: 74.
 Pean ChA, Kingery MT, Strauss E, Bosco JA, Halbrecht J. Direct-to-consumer advertising of stem cell clinics: Ethical considerations and recommendations for the health-care community. J Bone Joint Surg Am 2019; 101: e103.
 Chen L, Guo S, Wei C, Li H, Wang H, Xu Y. Effect of stem cell transplantation of premature ovarian failure in animal models and patients: A meta-analysis and case report. Exp Ther Med 2018; 15: 4105–4118.
 Ciccocioppo R, Cantore A, Chaimov D, Orlando G. Regenerative medicine: The red planet for clinicians. Intern Emerg Med 2019; 14: 911–921.
 Herraiz S, Buigues A, Díaz-García C, Romeu M, Martínez S, Gómez-Seguí I, et al. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril 2018; 109: 908–918.
 Aguado BA, Mulyasasmita W, Su J, Lampe KJ, Heilshorn SC. Improving viability of stem cells during syringe needle flow through the design of hydrogel cell carriers. Tissue Eng Part A 2012; 18: 806–815.