Cell therapy for the treatment of reproductive diseases and infertility: an overview from the mechanism to the clinic alongside diagnostic methods

Abstract

Infertility is experienced by 8%–12% of adults in their reproductive period globally and has become a prevalent concern. Besides routine therapeutic methods, stem cells are rapidly being examined as viable alternative therapies in regenerative medicine and translational investigation. Remarkable progress has been made in understanding the biology and purpose of stem cells. The affected pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) are further studied for their possible use in reproductive medicine, particularly for infertility induced by premature ovarian insufficiency and azoospermia. Accordingly, this study discusses current developments in the use of some kinds of MSCs such as adipose-derived stem cells, bone marrow stromal cells, umbilical cord MSCs, and menstrual blood MSCs. These methods have been used to manage ovarian and uterine disorders, and each technique presents a novel method for the therapy of infertility.

Keywords

infertility / stem cell therapy / mesenchymal stem cells / pluripotent stem cells

References

[1] Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, Hinton RA, Coulson C, Lambert PA, Watt EM, Desai KM. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 1985; 291(6510): 1693–1697

[2] Deroux A, Dumestre-Perard C, Dunand-Faure C, Bouillet L, Hoffmann P. Female infertility and serum auto-antibodies: a systematic review. Clin Rev Allergy Immunol 2017; 53(1): 78–86

[3] Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, Jassem J, Dobaczewska D, Fjosne HE, Peralta O, Arriagada R, Holmqvist M, Maenpaa J; HABITS Study Group. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008; 100(7): 475–482

[4] Vermeulen RFM, Korse CM, Kenter GG, Brood-van Zanten MMA, Beurden MV. Safety of hormone replacement therapy following risk-reducing salpingo-oophorectomy: systematic review of literature and guidelines. Climacteric 2019; 22(4): 352–360

[5] Practice Committee of American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: an American Society for Reproductive Medicine Practice Committee opinion. Fertil Steril 2012; 97(4): 825–834

[6] Blum B, Benvenisty N. The tumorigenicity of human embryonic stem cells. Adv Cancer Res 2008; 100: 133–158

[7] Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315–317

[8] Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010; 28(3): 585–596

[9] Körbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter?. Blood 2001; 98(10): 2900–2908

[10] In’t Anker PS, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 2004; 22(7): 1338–1345

[11] Hansen KR, He AL, Styer AK, Wild RA, Butts S, Engmann L, Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Huang H, Santoro N, Eisenberg E, Zhang H; Eunice Kennedy Shriver National Institute of Child Health, Human Development Reproductive Medicine Network. Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulation-intrauterine insemination. Fertil Steril 2016; 105(6): 1575–1583.e2

[12] Asemota OA, Klatsky P. Access to infertility care in the developing world: the family promotion gap. Semin Reprod Med 2015; 33(1): 17–22

[13] 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(1): CD012103

[14] Kathrins M, Niederberger C. Diagnosis and treatment of infertility-related male hormonal dysfunction. Nat Rev Urol 2016; 13(6): 309–323

[15] Smith RP, Lipshultz LI, Kovac JR. Stem cells, gene therapy, and advanced medical management hold promise in the treatment of male infertility. Asian J Androl 2016; 18(3): 364

[16] Chen D, Gell JJ, Tao Y, Sosa E, Clark AT. Modeling human infertility with pluripotent stem cells. Stem Cell Res (Amst) 2017; 21: 187–192

[17] Volarevic V, Bojic S, Nurkovic J, Volarevic A, Ljujic B, Arsenijevic N, Lako M, Stojkovic M. Stem cells as new agents for the treatment of infertility: current and future perspectives and challenges. Biomed Res Int 2014; 2014: 507234

[18] Yoshinaga K, Nishikawa S, Ogawa M, Hayashi S, Kunisada T, Fujimoto T, Nishikawa S. Role of c-kit in mouse spermatogenesis: identification of spermatogonia as a specific site of c-kit expression and function. Development 1991; 113(2): 689–699

[19] Kawamura K, Kawamura N, Hsueh AJ. Activation of dormant follicles: a new treatment for premature ovarian failure?. Curr Opin Obstet Gynecol 2016; 28(3): 217–222

[20] Rozwadowska N, Fiszer D, Jedrzejczak P, Kosicki W, Kurpisz M. Interleukin-1 superfamily genes expression in normal or impaired human spermatogenesis. Genes Immun 2007; 8(2): 100–107

[21] Huleihel M, Lunenfeld E. Regulation of spermatogenesis by paracrine/autocrine testicular factors. Asian J Androl 2004; 6(3): 259–268

[22] Naylor CE, Bagnéris C, DeCaen PG, Sula A, Scaglione A, Clapham DE, Wallace BA. Molecular basis of ion permeability in a voltage-gated sodium channel. EMBO J 2016; 35(8): 820–830

[23] Fang F, Li Z, Zhao Q, Li H, Xiong C. Human induced pluripotent stem cells and male infertility: an overview of current progress and perspectives. Hum Reprod 2018; 33(2): 188–195

[24] Hou J, Yang S, Yang H, Liu Y, Liu Y, Hai Y, Chen Z, Guo Y, Gong Y, Gao WQ, Li Z, He Z. Generation of male differentiated germ cells from various types of stem cells. Reproduction 2014; 147(6): R179–R188

[25] Eguizabal C, Montserrat N, Vassena R, Barragan M, Garreta E, Garcia-Quevedo L, Vidal F, Giorgetti A, Veiga A, Izpisua Belmonte JC. Complete meiosis from human induced pluripotent stem cells. Stem Cells 2011; 29(8): 1186–1195

[26] Ramathal C, Durruthy-Durruthy J, Sukhwani M, Arakaki JE, Turek PJ, Orwig KE, Reijo Pera RA. Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. Cell Rep 2014; 7(4): 1284–1297

[27] Irie N, Weinberger L, Tang WW, Kobayashi T, Viukov S, Manor YS, Dietmann S, Hanna JH, Surani MA. SOX17 is a critical specifier of human primordial germ cell fate. Cell 2015; 160(1–2): 253–268

[28] Sasaki K, Yokobayashi S, Nakamura T, Okamoto I, Yabuta Y, Kurimoto K, Ohta H, Moritoki Y, Iwatani C, Tsuchiya H, Nakamura S, Sekiguchi K, Sakuma T, Yamamoto T, Mori T, Woltjen K, Nakagawa M, Yamamoto T, Takahashi K, Yamanaka S, Saitou M. Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell 2015; 17(2): 178–194

[29] Easley CA 4th, Phillips BT, McGuire MM, Barringer JM, Valli H, Hermann BP, Simerly CR, Rajkovic A, Miki T, Orwig KE, Schatten GP. Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep 2012; 2(3): 440–446

[30] Gell JJ, Clark AT. Restoring fertility with human induced pluripotent stem cells: are we there yet?. Cell Stem Cell 2018; 23(6): 777–779

[31] Sugawa F, Araúzo-Bravo MJ, Yoon J, Kim KP, Aramaki S, Wu G, Stehling M, Psathaki OE, Hübner K, Schöler HR. Human primordial germ cell commitment in vitro associates with a unique PRDM14 expression profile. EMBO J 2015; 34(8): 1009–1024

[32] Sallam HN, Sadek SS, Agameya AF. Assisted hatching—a meta-analysis of randomized controlled trials. J Assist Reprod Genet 2003; 20(8): 332–342

[33] Bharti D, Jang SJ, Lee SY, Lee SL, Rho GJ. In vitro generation of oocyte like cells and their in vivo efficacy: how far we have been succeeded. Cells 2020; 9(3): 557

[34] Wu P, Deng G, Sai X, Guo H, Huang H, Zhu P. Maturation strategies and limitations of induced pluripotent stem cell-derived cardiomyocytes. Biosci Rep 2021; 41(6): BSR20200833

[35] Lee AS, Tang C, Rao MS, Weissman IL, Wu JC. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med 2013; 19(8): 998–1004

[36] Fernandez Tde S, de Souza Fernandez C, Mencalha AL. Human induced pluripotent stem cells from basic research to potential clinical applications in cancer. Biomed Res Int 2013; 2013: 430290

[37] Samadani AA, Keymoradzdeh A, Shams S, Soleymanpour A, Rashidy-Pour A, Hashemian H, Vahidi S, Norollahi SE. CAR T-cells profiling in carcinogenesis and tumorigenesis: an overview of CAR T-cells cancer therapy. Int Immunopharmacol 2021; 90: 107201

[38] Naji A, Rouas-Freiss N, Durrbach A, Carosella ED, Sensébé L, Deschaseaux F. Concise review: combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy. Stem Cells 2013; 31(11): 2296–2303

[39] Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 2015; 17(1): 11–22

[40] Desai N, Rambhia P, Gishto A. Human embryonic stem cell cultivation: historical perspective and evolution of xeno-free culture systems. Reprod Biol Endocrinol 2015; 13(1): 9

[41] Kehler J, Hübner K, Garrett S, Schöler HR. Generating oocytes and sperm from embryonic stem cells. Semin Reprod Med 2005; 23(3): 222–233

[42] Yuan Y, Zhou Q, Wan H, Shen B, Wang X, Wang M, Feng C, Xie M, Gu T, Zhou T, Fu R, Huang X, Zhou Q, Sha J, Zhao XY. Generation of fertile offspring from Kit(w)/Kit(wv) mice through differentiation of gene corrected nuclear transfer embryonic stem cells. Cell Res 2015; 25(7): 851–863

[43] Wang J, Liu C, Fujino M, Tong G, Zhang Q, Li XK, Yan H. Stem cells as a resource for treatment of infertility-related diseases. Curr Mol Med 2019; 19(8): 539–546

[44] Kita K, Watanabe T, Ohsaka K, Hayashi H, Kubota Y, Nagashima Y, Aoki I, Taniguchi H, Noce T, Inoue K, Miki H, Ogonuki N, Tanaka H, Ogura A, Ogawa T. Production of functional spermatids from mouse germline stem cells in ectopically reconstituted seminiferous tubules. Biol Reprod 2007; 76(2): 211–217

[45] Kubota H, Brinster RL. Spermatogonial stem cells. Biol Reprod 2018; 99(1): 52–74

[46] De Kretser DM, Baker HW. Infertility in men: recent advances and continuing controversies. J Clin Endocrinol Metab 1999; 84(10): 3443–3450

[47] Kanatsu-Shinohara M, Lee J, Inoue K, Ogonuki N, Miki H, Toyokuni S, Ikawa M, Nakamura T, Ogura A, Shinohara T. Pluripotency of a single spermatogonial stem cell in mice. Biol Reprod 2008; 78(4): 681–687

[48] McLean DJ. Spermatogonial stem cell transplantation and testicular function. Cell Tissue Res 2005; 322(1): 21–31

[49] Guan K, Nayernia K, Maier LS, Wagner S, Dressel R, Lee JH, Nolte J, Wolf F, Li M, Engel W, Hasenfuss G. Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 2006; 440(7088): 1199–1203

[50] Hamra FK, Schultz N, Chapman KM, Grellhesl DM, Cronkhite JT, Hammer RE, Garbers DL. Defining the spermatogonial stem cell. Dev Biol 2004; 269(2): 393–410

[51] Izadyar F, Wong J, Maki C, Pacchiarotti J, Ramos T, Howerton K, Yuen C, Greilach S, Zhao HH, Chow M, Chow YC, Rao J, Barritt J, Bar-Chama N, Copperman A. Identification and characterization of repopulating spermatogonial stem cells from the adult human testis. Hum Reprod 2011; 26(6): 1296–1306

[52] Hermann BP, Sukhwani M, Winkler F, Pascarella JN, Peters KA, Sheng Y, Valli H, Rodriguez M, Ezzelarab M, Dargo G, Peterson K, Masterson K, Ramsey C, Ward T, Lienesch M, Volk A, Cooper DK, Thomson AW, Kiss JE, Penedo MC, Schatten GP, Mitalipov S, Orwig KE. Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm. Cell Stem Cell 2012; 11(5): 715–726

[53] Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci USA 2006; 103(8): 2474–2479

[54] Griswold MD. The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol 1998; 9(4): 411–416

[55] Byskov AG, Fenger M, Westergaard L, Andersen CY. Forskolin and the meiosis inducing substance synergistically initiate meiosis in fetal male germ cells. Mol Reprod Dev 1993; 34(1): 47–52

[56] Zhu Y, Hu HL, Li P, Yang S, Zhang W, Ding H, Tian RH, Ning Y, Zhang LL, Guo XZ, Shi ZP, Li Z, He Z. Generation of male germ cells from induced pluripotent stem cells (iPS cells): an in vitro and in vivo study. Asian J Androl 2012; 14(4): 574–579

[57] Easley CA 4th, Simerly CR, Schatten G. Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility?. Reprod Biomed Online 2013; 27(1): 75–80

[58] Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004; 428(6979): 145–150

[59] White YA, Woods DC, Takai Y, Ishihara O, Seki H, Tilly JL. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat Med 2012; 18(3): 413–421

[60] Dunlop CE, Telfer EE, Anderson RA. Ovarian stem cells—potential roles in infertility treatment and fertility preservation. Maturitas 2013; 76(3): 279–283

[61] Oatley J, Hunt PA. Of mice and (wo)men: purified oogonial stem cells from mouse and human ovaries. Biol Reprod 2012; 86(6): 196

[62] Niikura Y, Niikura T, Tilly JL. Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment. Aging (Albany NY) 2009; 1(12): 971–978

[63] Anderson RA, Wallace WHB. Fertility preservation in girls and young women. Clin Endocrinol (Oxf) 2011; 75(4): 409–419

[64] Prianishnikov VA. On the concept of stem cell and a model of functional-morphological structure of the endometrium. Contraception 1978; 18(3): 213–223

[65] Chan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod 2004; 70(6): 1738–1750

[66] Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod 2009; 80(6): 1136–1145

[67] de Miguel-Gómez L, López-Martínez S, Francés-Herrero E, Rodríguez-Eguren A, Pellicer A, Cervelló I. Stem cells and the endometrium: from the discovery of adult stem cells to pre-clinical models. Cells 2021; 10(3): 595

[68] Akbar Samadani A, Keymoradzdeh A, Shams S, Soleymanpour A, Elham Norollahi S, Vahidi S, Rashidy-Pour A, Ashraf A, Mirzajani E, Khanaki K, Rahbar Taramsari M, Samimian S, Najafzadeh A. Mechanisms of cancer stem cell therapy. Clin Chim Acta 2020; 510: 581–592

[69] Rahimi S, Roushandeh AM, Ebrahimi A, Samadani AA, Kuwahara Y, Roudkenar MH. CRISPR/Cas9-mediated knockout of Lcn2 effectively enhanced CDDP-induced apoptosis and reduced cell migration capacity of PC3 cells. Life Sci 2019; 231: 116586

[70] Lapidot T, Petit I. Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 2002; 30(9): 973–981

[71] Azizi R, Aghebati-Maleki L, Nouri M, Marofi F, Negargar S, Yousefi M. Stem cell therapy in Asherman syndrome and thin endometrium: stem cell-based therapy. Biomed Pharmacother 2018; 102: 333–343

[72] Kato K, Yoshimoto M, Kato K, Adachi S, Yamayoshi A, Arima T, Asanoma K, Kyo S, Nakahata T, Wake N. Characterization of side-population cells in human normal endometrium. Hum Reprod 2007; 22(5): 1214–1223

[73] Meng X, Ichim TE, Zhong J, Rogers A, Yin Z, Jackson J, Wang H, Ge W, Bogin V, Chan KW, Thébaud B, Riordan NH. Endometrial regenerative cells: a novel stem cell population. J Transl Med 2007; 5(1): 57

[74] Gargett CE, Rogers PA. Human endometrial angiogenesis. Reproduction 2001; 121(2): 181–186

[75] Numao A, Hosono K, Suzuki T, Hayashi I, Uematsu S, Akira S, Ogino Y, Kawauchi H, Unno N, Majima M. The inducible prostaglandin E synthase mPGES-1 regulates growth of endometrial tissues and angiogenesis in a mouse implantation model. Biomed Pharmacother 2011; 65(1): 77–84

[76] Wolff EF, Mutlu L, Massasa EE, Elsworth JD, Eugene Redmond D Jr, Taylor HS. Endometrial stem cell transplantation in MPTP-exposed primates: an alternative cell source for treatment of Parkinson’s disease. J Cell Mol Med 2015; 19(1): 249–256

[77] Santamaria X, Massasa EE, Feng Y, Wolff E, Taylor HS. Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes. Mol Ther 2011; 19(11): 2065–2071

[78] Xie Q, Xiong X, Xiao N, He K, Chen M, Peng J, Su X, Mei H, Dai Y, Wei D, Lin G, Cheng L. Mesenchymal stem cells alleviate DHEA-induced polycystic ovary syndrome (PCOS) by inhibiting inflammation in mice. Stem Cells Int 2019; 2019: 9782373

[79] 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(1): 7

[80] Song D, Zhong Y, Qian C, Zou Q, Ou J, Shi Y, Gao L, Wang G, Liu Z, Li H, Ding H, Wu H, Wang F, Wang J, Li H. Human umbilical cord mesenchymal stem cells therapy in cyclophosphamide-induced premature ovarian failure rat model. Biomed Res Int 2016; 2016: 2517514

[81] 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(4): 370–382

[82] Zhang C. The roles of different stem cells in premature ovarian failure. Curr Stem Cell Res Ther 2020; 15(6): 473–481

[83] Shi Q, Gao J, Jiang Y, Sun B, Lu W, Su M, Xu Y, Yang X, Zhang Y. Differentiation of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells into endometrial cells. Stem Cell Res Ther 2017; 8(1): 246

[84] Zhang L, Li Y, Guan CY, Tian S, Lv XD, Li JH, Ma X, Xia HF. Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase. Stem Cell Res Ther 2018; 9(1): 36

[85] Xu L, Ding L, Wang L, Cao Y, Zhu H, Lu J, Li X, Song T, Hu Y, Dai J. Umbilical cord-derived mesenchymal stem cells on scaffolds facilitate collagen degradation via upregulation of MMP-9 in rat uterine scars. Stem Cell Res Ther 2017; 8(1): 84

[86] Ding L, Yan G, Wang B, Xu L, Gu Y, Ru T, Cui X, Lei L, Liu J, Sheng X, Wang B, Zhang C, Yang Y, Jiang R, Zhou J, Kong N, Lu F, Zhou H, Zhao Y, Chen B, Hu Y, Dai J, Sun H. Transplantation of UC-MSCs on collagen scaffold activates follicles in dormant ovaries of POF patients with long history of infertility. Sci China Life Sci 2018; 61(12): 1554–1565

[87] 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(4): 1029–1036

[88] Steigman SA, Ahmed A, Shanti RM, Tuan RS, Valim C, Fauza DO. Sternal repair with bone grafts engineered from amniotic mesenchymal stem cells. J Pediatr Surg 2009; 44(6): 1120–1126

[89] Kunisaki SM, Fuchs JR, Kaviani A, Oh JT, LaVan DA, Vacanti JP, Wilson JM, Fauza DO. Diaphragmatic repair through fetal tissue engineering: a comparison between mesenchymal amniocyte- and myoblast-based constructs. J Pediatr Surg 2006; 41(1): 34–39

[90] Xiao GY, Liu IH, Cheng CC, Chang CC, Lee YH, Cheng WT, Wu SC. Amniotic fluid stem cells prevent follicle atresia and rescue fertility of mice with premature ovarian failure induced by chemotherapy. PLoS One 2014; 9(9): e106538

[91] Liu T, Huang Y, Guo L, Cheng W, Zou G. CD44⁺/CD105⁺ human amniotic fluid mesenchymal stem cells survive and proliferate in the ovary long-term in a mouse model of chemotherapy-induced premature ovarian failure. Int J Med Sci 2012; 9(7): 592–602

[92] Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K, Bae YC, Jung JS. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 2004; 14(4–6): 311–324

[93] Damous LL, Nakamuta JS, Carvalho AE, Carvalho KC, Soares JM Jr, Simões MJ, Krieger JE, Baracat EC. Does adipose tissue-derived stem cell therapy improve graft quality in freshly grafted ovaries?. Reprod Biol Endocrinol 2015; 13(1): 108

[94] Sun M, Wang S, Li Y, Yu L, Gu F, Wang C, Yao Y. Adipose-derived stem cells improved mouse ovary function after chemotherapy-induced ovary failure. Stem Cell Res Ther 2013; 4(4): 80

[95] Kilic S, Yuksel B, Pinarli F, Albayrak A, Boztok B, Delibasi T. Effect of stem cell application on Asherman syndrome, an experimental rat model. J Assist Reprod Genet 2014; 31(8): 975–982

[96] Ling L, Feng X, Wei T, Wang Y, Wang Y, Wang Z, Tang D, Luo Y, Xiong Z. Human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation improves ovarian function in rats with premature ovarian insufficiency (POI) at least partly through a paracrine mechanism. Stem Cell Res Ther 2019; 10(1): 46

[97] Feng X, Ling L, Zhang W, Liu X, Wang Y, Luo Y, Xiong Z. Effects of human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation in situ on primary ovarian insufficiency in SD rats. Reprod Sci 2020; 27(7): 1502–1512

[98] Yin N, Wang Y, Lu X, Liu R, Zhang L, Zhao W, Yuan W, Luo Q, Wu H, Luan X, Zhang H. hPMSC transplantation restoring ovarian function in premature ovarian failure mice is associated with change of Th17/Tc17 and Th17/Treg cell ratios through the PI3K/Akt signal pathway. Stem Cell Res Ther 2018; 9(1): 37

[99] Li H, Zhao W, Wang L, Luo Q, Yin N, Lu X, Hou Y, Cui J, Zhang H. Human placenta-derived mesenchymal stem cells inhibit apoptosis of granulosa cells induced by IRE1α pathway in autoimmune POF mice. Cell Biol Int 2019; 43(8): 899–909

[100] Kim TH, Choi JH, Jun Y, Lim SM, Park S, Paek JY, Lee SH, Hwang JY, Kim GJ. 3D-cultured human placenta-derived mesenchymal stem cell spheroids enhance ovary function by inducing folliculogenesis. Sci Rep 2018; 8(1): 15313

[101] Qu HM, Qu LP, Pan XZ, Mu LS. Upregulated miR-222 targets BCL2L11 and promotes apoptosis of mesenchymal stem cells in preeclampsia patients in response to severe hypoxia. Int J Clin Exp Pathol 2018; 11(1): 110–119

[102] Manshadi MD, Navid S, Hoshino Y, Daneshi E, Noory P, Abbasi M. The effects of human menstrual blood stem cells-derived granulosa cells on ovarian follicle formation in a rat model of premature ovarian failure. Microsc Res Tech 2019; 82(6): 635–642

[103] Domnina A, Novikova P, Obidina J, Fridlyanskaya I, Alekseenko L, Kozhukharova I, Lyublinskaya O, Zenin V, Nikolsky N. Human mesenchymal stem cells in spheroids improve fertility in model animals with damaged endometrium. Stem Cell Res Ther 2018; 9(1): 50

[104] Zheng SX, Wang J, Wang XL, Ali A, Wu LM, Liu YS. Feasibility analysis of treating severe intrauterine adhesions by transplanting menstrual blood-derived stem cells. Int J Mol Med 2018; 41(4): 2201–2212

[105] 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(1): 61

[106] Yan Z, Guo F, Yuan Q, Shao Y, Zhang Y, Wang H, Hao S, Du X. 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(1): 4

[107] Tan J, Li P, Wang Q, Li Y, Li X, Zhao D, Xu X, Kong L. Autologous menstrual blood-derived stromal cells transplantation for severe Asherman’s syndrome. Hum Reprod 2016; 31(12): 2723–2729

[108] Owen M, Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp 1988; 136: 42–60

[109] Gao L, Huang Z, Lin H, Tian Y, Li P, Lin S. Bone marrow mesenchymal stem cells (BMSCs) restore functional endometrium in the rat model for severe Asherman syndrome. Reprod Sci 2019; 26(3): 436–444

[110] Besikcioglu HE, Sarıbas GS, Ozogul C, Tiryaki M, Kilic S, Pınarlı FA, Gulbahar O. 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(1): 53–59

[111] Guillot PV, Gotherstrom C, Chan J, Kurata H, Fisk NM. Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC. Stem Cells 2007; 25(3): 646–654

[112] Wang J, Ju B, Pan C, Gu Y, Zhang Y, Sun L, Zhang B, Zhang Y. Application of bone marrow-derived mesenchymal stem cells in the treatment of intrauterine adhesions in rats. Cell Physiol Biochem 2016; 39(4): 1553–1560

[113] Santamaria X, Cabanillas S, Cervelló I, Arbona C, Raga F, Ferro J, Palmero J, Remohí J, Pellicer A, Simón C. Autologous cell therapy with CD133⁺ bone marrow-derived stem cells for refractory Asherman’s syndrome and endometrial atrophy: a pilot cohort study. Hum Reprod 2016; 31(5): 1087–1096

[114] Cocuzza M, Alvarenga C, Pagani R. The epidemiology and etiology of azoospermia. Clinics (São Paulo) 2013; 68(Suppl 1): 15–26

[115] Vij SC, Sabanegh E Jr, Agarwal A. Biological therapy for non-obstructive azoospermia. Expert Opin Biol Ther 2018; 18(1): 19–23

[116] Kanatsu-Shinohara M, Shinohara T. Spermatogonial stem cell self-renewal and development. Annu Rev Cell Dev Biol 2013; 29(1): 163–187

[117] Brinster RL, Zimmermann JW. Spermatogenesis following male germ-cell transplantation. Proc Natl Acad Sci USA 1994; 91(24): 11298–11302

[118] Nayernia K, Nolte J, Michelmann HW, Lee JH, Rathsack K, Drusenheimer N, Dev A, Wulf G, Ehrmann IE, Elliott DJ, Okpanyi V, Zechner U, Haaf T, Meinhardt A, Engel W. In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev Cell 2006; 11(1): 125–132

[119] Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 2011; 146(4): 519–532

[120] Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, Welt CK; Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013; 98(12): 4565–4592

[121] Chugh R, Ashour D, Garcia N, Park H, Takala H, Ismail N, McAllister J, Al-Hendy A, El Andaloussi A. Towards cell therapy of polycystic ovary syndrome (PCOS): human mesenchymal stem cells secretome inhibits androgen production by pcos theca cells. Cytotherapy 2019; 21(5): S81

[122] Yin M, Wang X, Yao G, Lü M, Liang M, Sun Y, Sun F. Transactivation of micrornA-320 by microRNA-383 regulates granulosa cell functions by targeting E2F1 and SF-1 proteins. J Biol Chem 2014; 289(26): 18239–18257

[123] Verkauf BS. Incidence, symptoms, and signs of endometriosis in fertile and infertile women. J Fla Med Assoc 1987; 74(9): 671–675

[124] Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril 2012; 98(3): 591–598

[125] Macer ML, Taylor HS. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am 2012; 39(4): 535–549

[126] Liu Y, Kodithuwakku SP, Ng PY, Chai J, Ng EH, Yeung WS, Ho PC, Lee KF. Excessive ovarian stimulation up-regulates the Wnt-signaling molecule DKK1 in human endometrium and may affect implantation: an in vitro co-culture study. Hum Reprod 2010; 25(2): 479–490

[127] Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 2006; 2006(1): CD004635

[128] Benschop L, Farquhar C, van der Poel N, Heineman MJ. Interventions for women with endometrioma prior to assisted reproductive technology. Cochrane Database Syst Rev 2010; (11): CD008571

[129] European Society for Human Reproduction, Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, Cifkova R, de Muinck Keizer-Schrama S, Hogervorst E, Janse F, Liao L, Vlaisavljevic V, Zillikens C, Vermeulen N. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod 2016; 31(5): 926–937

[130] Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, Ho CH, Kawamura N, Tamura M, Hashimoto S, Sugishita Y, Morimoto Y, Hosoi Y, Yoshioka N, Ishizuka B, Hsueh AJ. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci USA 2013; 110(43): 17474–17479

[131] Asherman JG. Traumatic intra-uterine adhesions. J Obstet Gynaecol Br Emp 1950; 57(6): 892–896

[132] Schenker JG, Margalioth EJ. Intrauterine adhesions: an updated appraisal. Fertil Steril 1982; 37(5): 593–610

[133] Valle RF, Sciarra JJ. Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome. Am J Obstet Gynecol 1988; 158(6): 1459–1470

[134] Sugimoto O. Diagnostic and therapeutic hysteroscopy for traumatic intrauterine adhesions. Am J Obstet Gynecol 1978; 131(5): 539–547

[135] Zikopoulos KA, Kolibianakis EM, Platteau P, de Munck L, Tournaye H, Devroey P, Camus M. Live delivery rates in subfertile women with Asherman’s syndrome after hysteroscopic adhesiolysis using the resectoscope or the Versapoint system. Reprod Biomed Online 2004; 8(6): 720–725

[136] Alawadhi F, Du H, Cakmak H, Taylor HS. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman’s syndrome. PLoS One 2014; 9(5): e96662

[137] Gan L, Duan H, Xu Q, Tang YQ, Li JJ, Sun FQ, Wang S. Human amniotic mesenchymal stromal cell transplantation improves endometrial regeneration in rodent models of intrauterine adhesions. Cytotherapy 2017; 19(5): 603–616

[138] Singh N, Mohanty S, Seth T, Shankar M, Bhaskaran S, Dharmendra S. Autologous stem cell transplantation in refractory Asherman’s syndrome: a novel cell based therapy. J Hum Reprod Sci 2014; 7(2): 93–98

[139] Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci 2017; 18(9): 1852

[140] Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant 2011; 20(1): 5–14

[141] Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells—current trends and future prospective. Biosci Rep 2015; 35(2): e00191

[142] Sneddon JB, Tang Q, Stock P, Bluestone JA, Roy S, Desai T, Hebrok M. Stem cell therapies for treating diabetes: progress and remaining challenges. Cell Stem Cell 2018; 22(6): 810–823

[143] Du H, Taylor HS. Stem cells and female reproduction. Reprod Sci 2009; 16(2): 126–139

[144] Liu F, Hu S, Yang H, Li Z, Huang K, Su T, Wang S, Cheng K. Hyaluronic acid hydrogel integrated with mesenchymal stem cell-secretome to treat endometrial injury in a rat model of Asherman’s syndrome. Adv Healthc Mater 2019; 8(14): e1900411

[145] Mendt M, Rezvani K, Shpall E. Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant 2019; 54(Suppl 2): 789–792

[146] Ullah M, Qiao Y, Concepcion W, Thakor AS. Stem cell-derived extracellular vesicles: role in oncogenic processes, bioengineering potential, and technical challenges. Stem Cell Res Ther 2019; 10(1): 347

[147] Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borràs FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MÁ, Brigstock DR, Brisson A, Broekman ML, Bromberg JF, Bryl-Górecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzás EI, Byrd JB, Camussi G, Carter DR, Caruso S, Chamley LW, Chang YT, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FA, Coyle B, Crescitelli R, Criado MF, D’Souza-Schorey C, Das S, Datta Chaudhuri A, de Candia P, De Santana EF, De Wever O, Del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TA, Duarte FV, Duncan HM, Eichenberger RM, Ekström K, El Andaloussi S, Elie-Caille C, Erdbrügger U, Falcón-Pérez JM, Fatima F, Fish JE, Flores-Bellver M, Försönits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gámez-Valero A, Gardiner C, Gärtner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Görgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH,Hoffmann KF,Holder B,Holthofer H,Hosseinkhani B,Hu G,Huang Y,Huber V, Hunt S,Ibrahim AG,Ikezu T,Inal JM,Isin M, Ivanova A,Jackson HK,Jacobsen S,Jay SM,Jayachandran M,Jenster G,Jiang L,Johnson SM, Jones JC,Jong A,Jovanovic-Talisman T, Jung S,Kalluri R, Kano SI, Kaur S,Kawamura Y,Keller ET,Khamari D,Khomyakova E,Khvorova A,Kierulf P,Kim KP, Kislinger T,Klingeborn M,Klinke DJ 2nd,Kornek M, Kosanović MM,KovácsÁF, Krämer-Albers EM, Krasemann S,Krause M,Kurochkin IV,Kusuma GD, Kuypers S,Laitinen S,Langevin SM,Languino LR,Lannigan J,Lässer C,Laurent LC,Lavieu G, Lázaro-Ibáñez E, Le Lay S, Lee MS, Lee YXF,Lemos DS,Lenassi M, Leszczynska A,Li IT,Liao K, Libregts SF,Ligeti E,Lim R,Lim SK,Linē A,Linnemannstöns K, Llorente A,Lombard CA,Lorenowicz MJ,LörinczÁM,Lötvall J, Lovett J, Lowry MC,Loyer X, Lu Q,Lukomska B,Lunavat TR,Maas SL,Malhi H, Marcilla A,Mariani J,Mariscal J,Martens-Uzunova ES,Martin-Jaular L,Martinez MC,Martins VR,Mathieu M, Mathivanan S,Maugeri M,McGinnis LK,McVey MJ,Meckes DG Jr,Meehan KL, Mertens I,Minciacchi VR,Möller A,Møller Jørgensen M, Morales-Kastresana A,Morhayim J,Mullier F,Muraca M,Musante L, Mussack V,Muth DC,Myburgh KH,Najrana T,Nawaz M, Nazarenko I,Nejsum P,Neri C,Neri T,Nieuwland R,Nimrichter L,Nolan JP,Nolte-’t Hoen EN,Noren Hooten N,O’Driscoll L,O’Grady T,O’Loghlen A,Ochiya T,Olivier M, Ortiz A,Ortiz LA,Osteikoetxea X,Østergaard O,Ostrowski M,Park J,Pegtel DM,Peinado H, Perut F,Pfaffl MW,Phinney DG,Pieters BC,Pink RC, Pisetsky DS,Pogge von Strandmann E,Polakovicova I,Poon IK,Powell BH,Prada I, Pulliam L,Quesenberry P,Radeghieri A,Raffai RL,Raimondo S,Rak J,Ramirez MI,Raposo G, Rayyan MS,Regev-Rudzki N,Ricklefs FL,Robbins PD,Roberts DD, Rodrigues SC,Rohde E,Rome S, Rouschop KM,Rughetti A,Russell AE,Saá P,Sahoo S, Salas-Huenuleo E,Sánchez C,Saugstad JA,Saul MJ,Schiffelers RM,Schneider R,Schøyen TH,Scott A,Shahaj E, Sharma S,Shatnyeva O,Shekari F,Shelke GV,Shetty AK, Shiba K,Siljander PR,Silva AM,Skowronek A,Snyder OL 2nd, Soares RP, Sódar BW,Soekmadji C,Sotillo J,Stahl PD,Stoorvogel W,Stott SL,Strasser EF,Swift S, Tahara H,Tewari M,Timms K,Tiwari S,Tixeira R, Tkach M,Toh WS,Tomasini R,Torrecilhas AC,Tosar JP, Toxavidis V,Urbanelli L,Vader P,van Balkom BW,van der Grein SG,Van Deun J,van Herwijnen MJ,Van Keuren-Jensen K, van Niel G, van Royen ME,van Wijnen AJ,Vasconcelos MH,Vechetti IJ Jr,Veit TD, Vella LJ,Velot É,Verweij FJ,Vestad B,Viñas JL,Visnovitz T,Vukman KV,Wahlgren J,Watson DC,Wauben MH,Weaver A, Webber JP,Weber V,Wehman AM,Weiss DJ,Welsh JA, Wendt S,Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yáñez-Mó M, Yin H, Yuana Y, Zappulli V, Zarubova J, Žėkas V, Zhang JY, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7(1): 1535750

[148] Zhao AG, Shah K, Cromer B, Sumer H. Mesenchymal stem cell-derived extracellular vesicles and their therapeutic potential. Stem Cells Int 2020; 2020: 8825771

[149] Yu Y, Lin X, Wang Q, He M, Chau Y. Long-term therapeutic effect in nonhuman primate eye from a single injection of anti-VEGF controlled release hydrogel. Bioeng Transl Med 2019; 4(2): e10128

[150] Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol 2015; 77(1): 13–27

[151] Qiu G, Zheng G, Ge M, Wang J, Huang R, Shu Q, Xu J. Functional proteins of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther 2019; 10(1): 359

[152] Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013; 200(4): 373–383

[153] Joo HS, Suh JH, Lee HJ, Bang ES, Lee JM. Current knowledge and future perspectives on mesenchymal stem cell-derived exosomes as a new therapeutic agent. Int J Mol Sci 2020; 21(3): 727

[154] Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour A, Yousefi M. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles: a novel therapeutic paradigm. J Cell Physiol 2020; 235(2): 706–717

[155] Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, Stolz DB, Watkins SC, Di YP, Leikauf GD, Kolls J, Riches DW, Deiuliis G, Kaminski N, Boregowda SV, McKenna DH, Ortiz LA. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 2015; 6(1): 8472

[156] Domniz N, Meirow D. Premature ovarian insufficiency and autoimmune diseases. Best Pract Res Clin Obstet Gynaecol 2019; 60: 42–55

[157] De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010; 376(9744): 911–921

[158] Huang B, Qian C, Ding C, Meng Q, Zou Q, Li H. Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting MT1. Stem Cell Res Ther 2019; 10(1): 362

[159] Kim EH, Jeon BH, Kim J, Kim YM, Han Y, Ahn K, Cheong HK. Exposure to phthalates and bisphenol A are associated with atopic dermatitis symptoms in children: a time-series analysis. Environ Health 2017; 16(1): 24

[160] Ford EA, Beckett EL, Roman SD, McLaughlin EA, Sutherland JM. Advances in human primordial follicle activation and premature ovarian insufficiency. Reproduction 2020; 159(1): R15–R29

[161] Huhtaniemi I, Hovatta O, La Marca A, Livera G, Monniaux D, Persani L, Heddar A, Jarzabek K, Laisk-Podar T, Salumets A, Tapanainen JS, Veitia RA, Visser JA, Wieacker P, Wolczynski S, Misrahi M. Advances in the molecular pathophysiology, genetics, and treatment of primary ovarian insufficiency. Trends Endocrinol Metab 2018; 29(6): 400–419

[162] Wesevich V, Kellen AN, Pal L. Recent advances in understanding primary ovarian insufficiency. F1000 Res 2020; 9: F1000 Faculty Rev-1101

[163] Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, Harrison W, Vaiman D, Ben-Neriah Z, García-Tuñón I, Fellous M, Pendás AM, Veitia RA, Vilain E. Mutant cohesin in premature ovarian failure. N Engl J Med 2014; 370(10): 943–949

[164] Bouilly J, Beau I, Barraud S, Bernard V, Azibi K, Fagart J, Fèvre A, Todeschini AL, Veitia RA, Beldjord C, Delemer B, Dodé C, Young J, Binart N. Identification of multiple gene mutations accounts for a new genetic architecture of primary ovarian insufficiency. J Clin Endocrinol Metab 2016; 101(12): 4541–4550

[165] Jaillard S, Bell K, Akloul L, Walton K, McElreavy K, Stocker WA, Beaumont M, Harrisson C, Jääskeläinen T, Palvimo JJ, Robevska G, Launay E, Satié AP, Listyasari N, Bendavid C, Sreenivasan R, Duros S, van den Bergen J, Henry C, Domin-Bernhard M, Cornevin L, Dejucq-Rainsford N, Belaud-Rotureau MA, Odent S, Ayers KL, Ravel C, Tucker EJ, Sinclair AH. New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing. Maturitas 2020; 141: 9–19

[166] Liu T, Liu Y, Huang Y, Chen J, Yu Z, Chen C, Lai L. miR-15b induces premature ovarian failure in mice via inhibition of α-Klotho expression in ovarian granulosa cells. Free Radic Biol Med 2019; 141: 383–392

[167] Persani L, Rossetti R, Cacciatore C, Fabre S. Genetic defects of ovarian TGF-β-like factors and premature ovarian failure. J Endocrinol Invest 2011; 34(3): 244–251

[168] Grosbois J, Demeestere I. Dynamics of PI3K and Hippo signaling pathways during in vitro human follicle activation. Hum Reprod 2018; 33(9): 1705–1714

[169] Dragojević-Dikić S, Marisavljević D, Mitrović A, Dikić S, Jovanović T, Janković-Raznatović S. An immunological insight into premature ovarian failure (POF). Autoimmun Rev 2010; 9(11): 771–774

[170] Coulam CB, Stern JJ. Immunology of ovarian failure. Am J Reprod Immunol 1991; 25(4): 169–174

[171] Shen M, Jiang Y, Guan Z, Cao Y, Li L, Liu H, Sun SC. Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy. Autophagy 2017; 13(8): 1364–1385

[172] 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(1): 216

[173] Zhang J, Yin H, Jiang H, Du X, Yang Z. The protective effects of human umbilical cord mesenchymal stem cell-derived extracellular vesicles on cisplatin-damaged granulosa cells. Taiwan J Obstet Gynecol 2020; 59(4): 527–533

[174] Yang Z, Du X, Wang C, Zhang J, Liu C, Li Y, Jiang H. Therapeutic effects of human umbilical cord mesenchymal stem cell-derived microvesicles on premature ovarian insufficiency in mice. Stem Cell Res Ther 2019; 10(1): 250

[175] Zhang S, Huang B, Su P, Chang Q, Li P, Song A, Zhao X, Yuan Z, Tan J. Concentrated exosomes from menstrual blood-derived stromal cells improves ovarian activity in a rat model of premature ovarian insufficiency. Stem Cell Res Ther 2021; 12(1): 178

[176] Xiao GY, Cheng CC, Chiang YS, Cheng WT, Liu IH, Wu SC. Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy. Sci Rep 2016; 6(1): 23120

[177] Sun L, Li D, Song K, Wei J, Yao S, Li Z, Su X, Ju X, Chao L, Deng X, Kong B, Li L. Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro. Sci Rep 2017; 7(1): 2552

[178] Boecker W, van Horn L, Stenman G, Stürken C, Schumacher U, Loening T, Liesenfeld L, Korsching E, Gläser D, Tiemann K, Buchwalow I. Spatially correlated phenotyping reveals K5-positive luminal progenitor cells and p63-K5/14-positive stem cell-like cells in human breast epithelium. Lab Invest 2018; 98(8): 1065–1075

[179] Thabet E, Yusuf A, Abdelmonsif DA, Nabil I, Mourad G, Mehanna RA. Extracellular vesicles miRNA-21: a potential therapeutic tool in premature ovarian dysfunction. Mol Hum Reprod 2020; 26(12): 906–919

[180] Sun B, Ma Y, Wang F, Hu L, Sun Y. miR-644-5p carried by bone mesenchymal stem cell-derived exosomes targets regulation of p53 to inhibit ovarian granulosa cell apoptosis. Stem Cell Res Ther 2019; 10(1): 360

[181] Ding C, Qian C, Hou S, Lu J, Zou Q, Li H, Huang B. Exosomal miRNA-320a is released from hAMSCs and regulates SIRT4 to prevent reactive oxygen species generation in POI. Mol Ther Nucleic Acids 2020; 21: 37–50

[182] Liu C, Yin H, Jiang H, Du X, Wang C, Liu Y, Li Y, Yang Z. Extracellular vesicles derived from mesenchymal stem cells recover fertility of premature ovarian insufficiency mice and the effects on their offspring. Cell Transplant 2020; 29: 963689720923575

[183] Norman RJ, Wu R, Stankiewicz MT. 4: Polycystic ovary syndrome. Med J Aust 2004; 180(3): 132–137

[184] Blázquez R, Sánchez-Margallo FM, Álvarez V, Matilla E, Hernández N, Marinaro F, Gómez-Serrano M, Jorge I, Casado JG, Macías-García B. Murine embryos exposed to human endometrial MSCs-derived extracellular vesicles exhibit higher VEGF/PDGF AA release, increased blastomere count and hatching rates. PLoS One 2018; 13(4): e0196080

[185] Marinaro F, Macías-García B, Sánchez-Margallo FM, Blázquez R, Álvarez V, Matilla E, Hernández N, Gómez-Serrano M, Jorge I, Vázquez J, González-Fernández L, Pericuesta E, Gutiérrez-Adán A, Casado JG. Extracellular vesicles derived from endometrial human mesenchymal stem cells enhance embryo yield and quality in an aged murine model. Biol Reprod 2019; 100(5): 1180–1192

[186] The Lancet Diabetes Endocrinology. Empowering women with PCOS. Lancet Diabetes Endocrinol 2019; 7(10): 737

[187] Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol 2018; 14(5): 270–284

[188] Liang X, Zhang L, Wang S, Han Q, Zhao RC. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci 2016; 129(11): 2182–2189

[189] Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, Stener-Victorin E, Fauser BC, Norman RJ, Teede H. 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(6): 687–708

[190] Madkour A, Bouamoud N, Kaarouch I, Louanjli N, Saadani B, Assou S, Aboulmaouahib S, Sefrioui O, Amzazi S, Copin H, Benkhalifa M. Follicular fluid and supernatant from cultured cumulus-granulosa cells improve in vitro maturation in patients with polycystic ovarian syndrome. Fertil Steril 2018; 110(4): 710–719

[191] Zhao Y, Tao M, Wei M, Du S, Wang H, Wang X. Mesenchymal stem cells derived exosomal miR-323-3p promotes proliferation and inhibits apoptosis of cumulus cells in polycystic ovary syndrome (PCOS). Artif Cells Nanomed Biotechnol 2019; 47(1): 3804–3813

[192] Salazar CA, Isaacson K, Morris S. A comprehensive review of Asherman’s syndrome: causes, symptoms and treatment options. Curr Opin Obstet Gynecol 2017; 29(4): 249–256

[193] March CM. Asherman’s syndrome. Semin Reprod Med 2011; 29(2): 83–94

[194] Lo ST, Ramsay P, Pierson R, Manconi F, Munro MG, Fraser IS. Endometrial thickness measured by ultrasound scan in women with uterine outlet obstruction due to intrauterine or upper cervical adhesions. Hum Reprod 2008; 23(2): 306–309

[195] Xiao S, Wan Y, Xue M, Zeng X, Xiao F, Xu D, Yang X, Zhang P, Sheng W, Xu J, Zhou S. Etiology, treatment, and reproductive prognosis of women with moderate-to-severe intrauterine adhesions. Int J Gynaecol Obstet 2014; 125(2): 121–124

[196] Bai X, Liu J, Cao S, Wang L. Mechanisms of endometrial fibrosis and the potential application of stem cell therapy. Discov Med 2019; 27(150): 267–279

[197] Santamaria X, Isaacson K, Simón C. Asherman’s syndrome: it may not be all our fault. Hum Reprod 2018; 33(8): 1374–1380

[198] Salma U, Xue M, Ali Sheikh MS, Guan X, Xu B, Zhang A, Huang L, Xu D. Role of transforming growth factor-β1 and Smads signaling pathway in intrauterine adhesion. Mediators Inflamm 2016; 2016: 4158287

[199] Wang X, Ma N, Sun Q, Huang C, Liu Y, Luo X. Elevated NF-κB signaling in Asherman syndrome patients and animal models. Oncotarget 2017; 8(9): 15399–15406

[200] Xue X, Chen Q, Zhao G, Zhao JY, Duan Z, Zheng PS. The overexpression of TGF-β and CCN2 in intrauterine adhesions involves the NF-κB signaling pathway. PLoS One 2015; 10(12): e0146159

[201] Zhu HY, Ge TX, Pan YB, Zhang SY. Advanced role of hippo signaling in endometrial fibrosis: implications for intrauterine adhesion. Chin Med J (Engl) 2017; 130(22): 2732–2737

[202] Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, Schneider H, Sadowski A, Riener MO, MacDougald OA, Distler O, Schett G, Distler JH. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun 2012; 3(1): 735

[203] Liu L, Chen G, Chen T, Shi W, Hu H, Song K, Huang R, Cai H, He Y. si-SNHG5-FOXF2 inhibits TGF-β1-induced fibrosis in human primary endometrial stromal cells by the Wnt/β-catenin signalling pathway. Stem Cell Res Ther 2020; 11(1): 1–17

[204] Chen G, Liu L, Sun J, Zeng L, Cai H, He Y. Foxf2 and Smad6 co-regulation of collagen 5A2 transcription is involved in the pathogenesis of intrauterine adhesion. J Cell Mol Med 2020; 24(5): 2802–2818

[205] Leung RKK, Lin Y, Liu Y. Recent advances in understandings towards pathogenesis and treatment for intrauterine adhesion and disruptive insights from single-cell analysis. Reprod Sci 2021; 28(7): 1812–1826

[206] Liu M, Zhao D, Wu X, Guo S, Yan L, Zhao S, Li H, Wang Y, Rong F. miR-466 and NUS1 regulate the AKT/nuclear factor kappa B (NFκB) signaling pathway in intrauterine adhesions in a rat model. Med Sci Monit 2019; 25: 4094–4103

[207] Xu Q, Duan H, Gan L, Liu X, Chen F, Shen X, Tang YQ, Wang S. MicroRNA-1291 promotes endometrial fibrosis by regulating the ArhGAP29-RhoA/ROCK1 signaling pathway in a murine model. Mol Med Rep 2017; 16(4): 4501–4510

[208] Zhu H, Pan Y, Jiang Y, Li J, Zhang Y, Zhang S. Activation of the Hippo/TAZ pathway is required for menstrual stem cells to suppress myofibroblast and inhibit transforming growth factor β signaling in human endometrial stromal cells. Hum Reprod 2019; 34(4): 635–645

[209] Zhao S, Qi W, Zheng J, Tian Y, Qi X, Kong D, Zhang J, Huang X. Exosomes derived from adipose mesenchymal stem cells restore functional endometrium in a rat model of intrauterine adhesions. Reprod Sci 2020; 27(6): 1266–1275

[210] Xin L, Lin X, Zhou F, Li C, Wang X, Yu H, Pan Y, Fei H, Ma L, Zhang S. A scaffold laden with mesenchymal stem cell-derived exosomes for promoting endometrium regeneration and fertility restoration through macrophage immunomodulation. Acta Biomater 2020; 113: 252–266

[211] Perrini C, Strillacci MG, Bagnato A, Esposti P, Marini MG, Corradetti B, Bizzaro D, Idda A, Ledda S, Capra E, Pizzi F, Lange-Consiglio A, Cremonesi F. Microvesicles secreted from equine amniotic-derived cells and their potential role in reducing inflammation in endometrial cells in an in-vitro model. Stem Cell Res Ther 2016; 7(1): 169

[212] Yao Y, Chen R, Wang G, Zhang Y, Liu F. Exosomes derived from mesenchymal stem cells reverse EMT via TGF-β1/Smad pathway and promote repair of damaged endometrium. Stem Cell Res Ther 2019; 10(1): 225

[213] Saribas GS, Ozogul C, Tiryaki M, Alpaslan Pinarli F, Hamdemir Kilic S. Effects of uterus derived mesenchymal stem cells and their exosomes on Asherman’s syndrome. Acta Histochem 2020; 122(1): 151465

[214] Chang Y, Liu Y, Li X. Exosomes derived from human umbilical cord mesenchymal stem cells promote proliferation of endometrial stromal cell. Fertil Steril 2020; 114(3): e530

[215] Aworunse OS, Adeniji O, Oyesola OL, Isewon I, Oyelade J, Obembe OO. Genomic interventions in medicine. Bioinform Biol Insights 2018; 12: 1177932218816100

[216] Goetz LH, Schork NJ. Personalized medicine: motivation, challenges, and progress. Fertil Steril 2018; 109(6): 952–963

[217] Zhang PY, Yu Y. Precise personalized medicine in gynecology cancer and infertility. Front Cell Dev Biol 2020; 7: 382

[218] Ferlin A, Arredi B, Foresta C. Genetic causes of male infertility. Reprod Toxicol 2006; 22(2): 133–141

[219] Bracke A, Peeters K, Punjabi U, Hoogewijs D, Dewilde S. A search for molecular mechanisms underlying male idiopathic infertility. Reprod Biomed Online 2018; 36(3): 327–339

[220] Ventimiglia E, Montorsi F, Salonia A. Comorbidities and male infertility: a worrisome picture. Curr Opin Urol 2016; 26(2): 146–151

[221] Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, Krausz C; European Association of Urology Working Group on Male Infertility. European Association of Urology guidelines on Male Infertility: the 2012 update. Eur Urol 2012; 62(2): 324–332

[222] Oud MS, Volozonoka L, Smits RM, Vissers LELM, Ramos L, Veltman JA. A systematic review and standardized clinical validity assessment of male infertility genes. Hum Reprod 2019; 34(5): 932–941

[223] Krausz C, Escamilla AR, Chianese C. Genetics of male infertility: from research to clinic. Reproduction 2015; 150(5): R159–R174

[224] Cariati F, D’Argenio V, Tomaiuolo R. The evolving role of genetic tests in reproductive medicine. J Transl Med 2019; 17(1): 267

[225] Krausz C, Degl’Innocenti S. Y chromosome and male infertility: update, 2006. Front Biosci 2006; 11(1): 3049–3061

[226] Kim IW, Khadilkar AC, Ko EY, Sabanegh ES Jr. 47, XYY syndrome and male infertility. Rev Urol 2013; 15(4): 188–196

[227] Krausz C, Hoefsloot L, Simoni M, Tüttelmann F; European Academy of Andrology; European Molecular Genetics Quality Network. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state-of-the-art 2013. Andrology 2014; 2(1): 5–19

[228] Stuppia L, Gatta V, Calabrese G, Guanciali Franchi P, Morizio E, Bombieri C, Mingarelli R, Sforza V, Frajese G, Tenaglia R, Palka G. A quarter of men with idiopathic oligo-azoospermia display chromosomal abnormalities and microdeletions of different types in interval 6 of Yq11. Hum Genet 1998; 102(5): 566–570

[229] Patsalis PC, Sismani C, Quintana-Murci L, Taleb-Bekkouche F, Krausz C, McElreavey K. Effects of transmission of Y chromosome AZFc deletions. Lancet 2002; 360(9341): 1222–1224

[230] Asero P, Calogero AE, Condorelli RA, Mongioi’ L, Vicari E, Lanzafame F, Crisci R, La Vignera S. Relevance of genetic investigation in male infertility. J Endocrinol Invest 2014; 37(5): 415–427

[231] Kuroda-Kawaguchi T, Skaletsky H, Brown LG, Minx PJ, Cordum HS, Waterston RH, Wilson RK, Silber S, Oates R, Rozen S, Page DC. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 2001; 29(3): 279–286

[232] Ferlin A, Garolla A, Foresta C. Chromosome abnormalities in sperm of individuals with constitutional sex chromosomal abnormalities. Cytogenet Genome Res 2005; 111(3–4): 310–316

[233] Schultz N, Hamra FK, Garbers DL. A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. Proc Natl Acad Sci USA 2003; 100(21): 12201–12206

[234] Mastantuoni E, Saccone G, Al-Kouatly HB, Paternoster M, D’Alessandro P, Arduino B, Carbone L, Esposito G, Raffone A, De Vivo V, Maruotti GM, Berghella V, Zullo F. Expanded carrier screening: a current perspective. Eur J Obstet Gynecol Reprod Biol 2018; 230: 41–54

[235] Morin SJ, Eccles J, Iturriaga A, Zimmerman RS. Translocations, inversions and other chromosome rearrangements. Fertil Steril 2017; 107(1): 19–26

[236] Folsom LJ, Fuqua JS. Reproductive issues in women with turner syndrome. Endocrinol Metab Clin North Am 2015; 44(4): 723–737

[237] Oktay K, Bedoschi G, Berkowitz K, Bronson R, Kashani B, McGovern P, Pal L, Quinn G, Rubin K. Fertility preservation in women with Turner syndrome: a comprehensive review and practical guidelines. J Pediatr Adolesc Gynecol 2016; 29(5): 409–416

[238] Chen M, Wei S, Hu J, Quan S. Can comprehensive chromosome screening technology improve IVF/ICSI outcomes? A meta-analysis.. PLoS One 2015; 10(10): e0140779

[239] Man L, Lekovich J, Rosenwaks Z, Gerhardt J. Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations. Front Mol Neurosci 2017; 10: 290

[240] Hoyos LR, Thakur M. Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency. J Assist Reprod Genet 2017; 34(3): 315–323

[241] Rossetti R, Ferrari I, Bonomi M, Persani L. Genetics of primary ovarian insufficiency. Clin Genet 2017; 91(2): 183–198

[242] Stavljenić-Rukavina A. 1. Prenatal diagnosis of chromosomal disorders—molecular aspects. EJIFCC 2008; 19(1): 2–6

[243] Bennett RL. The family medical history as a tool in preconception consultation. J Community Genet 2012; 3(3): 175–183

[244] Mathijssen IB, Holtkamp KCA, Ottenheim CPE, van Eeten-Nijman JMC, Lakeman P, Meijers-Heijboer H, van Maarle MC, Henneman L. Preconception carrier screening for multiple disorders: evaluation of a screening offer in a Dutch founder population. Eur J Hum Genet 2018; 26(2): 166–175

[245] Dorney E, Black KI. Preconception care. Aust J Gen Pract 2018; 47(7): 424–429

[246] Elce A, Boccia A, Cardillo G, Giordano S, Tomaiuolo R, Paolella G, Castaldo G. Three novel CFTR polymorphic repeats improve segregation analysis for cystic fibrosis. Clin Chem 2009; 55(7): 1372–1379

[247] Cariati F, Savarese M, D’Argenio V, Salvatore F, Tomaiuolo R. The SEeMORE strategy: single-tube electrophoresis analysis-based genotyping to detect monogenic diseases rapidly and effectively from conception until birth. Clin Chem Lab Med 2017; 56(1): 40–50

[248] Allyse M, Minear MA, Berson E, Sridhar S, Rote M, Hung A, Chandrasekharan S. Non-invasive prenatal testing: a review of international implementation and challenges. Int J Womens Health 2015; 7: 113–126

[249] Chiu EKL, Hui WWI, Chiu RWK. cfDNA screening and diagnosis of monogenic disorders—where are we heading?. Prenat Diagn 2018; 38(1): 52–58

[250] Saba L, Masala M, Capponi V, Marceddu G, Massidda M, Rosatelli MC. Non-invasive prenatal diagnosis of beta-thalassemia by semiconductor sequencing: a feasibility study in the sardinian population. Eur J Hum Genet 2017; 25(5): 600–607

[251] New MI, Tong YK, Yuen T, Jiang P, Pina C, Chan KC, Khattab A, Liao GJ, Yau M, Kim SM, Chiu RW, Sun L, Zaidi M, Lo YM. Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma. J Clin Endocrinol Metab 2014; 99(6): E1022–E1030

[252] Haahr MK, Jensen CH, Toyserkani NM, Andersen DC, Damkier P, Sørensen JA, Lund L, Sheikh SP. Safety and potential effect of a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase I clinical trial. EBioMedicine 2016; 5: 204–210

[253] Mashayekhi M, Mirzadeh E, Chekini Z, Ahmadi F, Eftekhari-Yazdi P, Vesali S, Madani T, Aghdami N. Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human. J Ovarian Res 2021; 14(1): 5

[254] Igboeli P, El Andaloussi A, Sheikh U, Takala H, ElSharoud A, McHugh A, Gavrilova-Jordan L, Levy S, Al-Hendy A. Intraovarian injection of autologous human mesenchymal stem cells increases estrogen production and reduces menopausal symptoms in women with premature ovarian failure: two case reports and a review of the literature. J Med Case Reports 2020; 14(1): 108

[255] Cheng YC, Takagi M, Milbourne A, Champlin RE, Ueno NT. Phase II study of gonadotropin-releasing hormone analog for ovarian function preservation in hematopoietic stem cell transplantation patients. Oncologist 2012; 17(2): 233–238

[256] Cao Y, Sun H, Zhu H, Zhu X, Tang X, Yan G, Wang J, Bai D, Wang J, Wang L, Zhou Q, Wang H, Dai C, Ding L, Xu B, Zhou Y, Hao J, Dai J, Hu Y. 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(1): 192

[257] Yang W, Zhang J, Xu B, He Y, Liu W, Li J, Zhang S, Lin X, Su D, Wu T, Li J. HucMSC-derived exosomes mitigate the age-related retardation of fertility in female mice. Mol Ther 2020; 28(4): 1200–1213

[258] Spinosa M, Lu G, Su G, Bontha SV, Gehrau R, Salmon MD, Smith JR, Weiss ML, Mas VR, Upchurch GR Jr, Sharma AK. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB J 2018; 32(11): 6038–6050

[259] Lo Sicco C, Reverberi D, Balbi C, Ulivi V, Principi E, Pascucci L, Becherini P, Bosco MC, Varesio L, Franzin C, Pozzobon M, Cancedda R, Tasso R. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med 2017; 6(3): 1018–1028

[260] Ding C, Zhu L, Shen H, Lu J, Zou Q, Huang C, Li H, Huang B. Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7. Stem Cells 2020; 38(9): 1137–1148

[261] Bodart-Santos V, de Carvalho LRP, de Godoy MA, Batista AF, Saraiva LM, Lima LG, Abreu CA, De Felice FG, Galina A, Mendez-Otero R, Ferreira ST. Extracellular vesicles derived from human Wharton’s jelly mesenchymal stem cells protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers. Stem Cell Res Ther 2019; 10(1): 332

[262] Chaubey S, Thueson S, Ponnalagu D, Alam MA, Gheorghe CP, Aghai Z, Singh H, Bhandari V. Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6. Stem Cell Res Ther 2018; 9(1): 173

[263] Yang C, Lim W, Park J, Park S, You S, Song G. Anti-inflammatory effects of mesenchymal stem cell-derived exosomal microRNA-146a-5p and microRNA-548e-5p on human trophoblast cells. Mol Hum Reprod 2019; 25(11): 755–771

[264] Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Zhao Y, Liu H, Fu X, Han W. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med 2015; 13(1): 308

[265] Alzubi MA, Sohal SS, Sriram M, Turner TH, Zot P, Idowu M, Harrell JC. Quantitative assessment of breast cancer liver metastasis expansion with patient-derived xenografts. Clin Exp Metastasis 2019; 36(3): 257–269

[266] Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, Montgomery EN, Mellema MS, Bardini RL, Contreras Z, Hoon M, Bauer G, Fink KD, Fury B, Hendrix KJ, Chedin F, El-Andaloussi S, Hwang B, Mulligan MS, Lehtiö J, Nolta JA. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells 2016; 34(3): 601–613

[267] Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal 2014; 12(1): 26

[268] Park KS, Svennerholm K, Shelke GV, Bandeira E, Lässer C, Jang SC, Chandode R, Gribonika I, Lötvall J. Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10. Stem Cell Res Ther 2019; 10(1): 231

[269] Gonzalez-King H, García NA, Ontoria-Oviedo I, Ciria M, Montero JA, Sepúlveda P. Hypoxia inducible factor-1α potentiates jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells 2017; 35(7): 1747–1759

[270] Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C, Millard RW, Xiao DS, Ashraf M, Xu M. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 2017; 8(28): 45200–45212

[271] Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, Shi H, Wu L, Zhu W, Qian H, Xu W. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells 2015; 33(7): 2158–2168

[272] Baek G, Choi H, Kim Y, Lee HC, Choi C. Mesenchymal stem cell-derived extracellular vesicles as therapeutics and as a drug delivery platform. Stem Cells Transl Med 2019; 8(9): 880–886

[273] Liu L, Liu Y, Feng C, Chang J, Fu R, Wu T, Yu F, Wang X, Xia L, Wu C, Fang B. Lithium-containing biomaterials stimulate bone marrow stromal cell-derived exosomal miR-130a secretion to promote angiogenesis. Biomaterials 2019; 192: 523–536

[274] Yang M, Lin L, Sha C, Li T, Zhao D, Wei H, Chen Q, Liu Y, Chen X, Xu W, Li Y, Zhu X. Bone marrow mesenchymal stem cell-derived exosomal miR-144-5p improves rat ovarian function after chemotherapy-induced ovarian failure by targeting PTEN. Lab Invest 2020; 100(3): 342–352

[275] Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, Gao L, Xie J, Xu B. Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc Res 2019; 115(7): 1205–1216

[276] Eirin A, Zhu XY, Puranik AS, Woollard JR, Tang H, Dasari S, Lerman A, van Wijnen AJ, Lerman LO. Comparative proteomic analysis of extracellular vesicles isolated from porcine adipose tissue-derived mesenchymal stem/stromal cells. Sci Rep 2016; 6(1): 36120

[277] Vrijsen KR, Maring JA, Chamuleau SA, Verhage V, Mol EA, Deddens JC, Metz CH, Lodder K, van Eeuwijk EC, van Dommelen SM, Doevendans PA, Smits AM, Goumans MJ, Sluijter JP. Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv Healthc Mater 2016; 5(19): 2555–2565

[278] Crain SK, Robinson SR, Thane KE, Davis AM, Meola DM, Barton BA, Yang VK, Hoffman AM. Extracellular vesicles from Wharton’s jelly mesenchymal stem cells suppress CD4 expressing T cells through transforming growth factor beta and adenosine signaling in a canine model. Stem Cells Dev 2019; 28(3): 212–226

[279] Mardpour S, Hamidieh AA, Taleahmad S, Sharifzad F, Taghikhani A, Baharvand H. Interaction between mesenchymal stromal cell-derived extracellular vesicles and immune cells by distinct protein content. J Cell Physiol 2019; 234(6): 8249–8258

[280] Merino-González C, Zuñiga FA, Escudero C, Ormazabal V, Reyes C, Nova-Lamperti E, Salomón C, Aguayo C. Mesenchymal stem cell-derived extracellular vesicles promote angiogenesis: potencial clinical application. Front Physiol 2016; 7: 24

[281] Tsuji K, Kitamura S, Wada J. Immunomodulatory and regenerative effects of mesenchymal stem cell-derived extracellular vesicles in renal diseases. Int J Mol Sci 2020; 21(3): 756

[282] Paduano F, Marrelli M, Palmieri F, Tatullo M. CD146 expression influences periapical cyst mesenchymal stem cell properties. Stem Cell Rev Rep 2016; 12(5): 592–603

[283] Momose T, Miyaji H, Kato A, Ogawa K, Yoshida T, Nishida E, Murakami S, Kosen Y, Sugaya T, Kawanami M. Collagen hydrogel scaffold and fibroblast growth factor-2 accelerate periodontal healing of class II furcation defects in dog. Open Dent J 2016; 10(1): 347–359

[284] Cervelló I, Gil-Sanchis C, Santamaría X, Cabanillas S, Díaz A, Faus A, Pellicer A, Simón C. Human CD133(+) bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome. Fertil Steril 2015; 104(6): 1552–60.e1-3

[285] Mohamed SA, Shalaby SM, Abdelaziz M, Brakta S, Hill WD, Ismail N, Al-Hendy A. Human mesenchymal stem cells partially reverse infertility in chemotherapy-induced ovarian failure. Reprod Sci 2018; 25(1): 51–63

[286] Abd-Allah SH, Shalaby SM, Pasha HF, El-Shal AS, Raafat N, Shabrawy SM, Awad HA, Amer MG, Gharib MA, El Gendy EA, Raslan AA, El-Kelawy HM. Mechanistic action of mesenchymal stem cell injection in the treatment of chemically induced ovarian failure in rabbits. Cytotherapy 2013; 15(1): 64–75

[287] Fan D, Wu S, Ye S, Wang W, Guo X, Liu Z. Umbilical cord mesenchyme stem cell local intramuscular injection for treatment of uterine niche: protocol for a prospective, randomized, double-blinded, placebo-controlled clinical trial. Medicine (Baltimore) 2017; 96(44): e8480

[288] Li J, Mao Q, He J, She H, Zhang Z, Yin C. Human umbilical cord mesenchymal stem cells improve the reserve function of perimenopausal ovary via a paracrine mechanism. Stem Cell Res Ther 2017; 8(1): 55

[289] Wang S, Yu L, Sun M, Mu S, Wang C, Wang D, Yao Y. The therapeutic potential of umbilical cord mesenchymal stem cells in mice premature ovarian failure. Biomed Res Int 2013; 2013: 690491

[290] Kilic S, Yuksel B, Pinarli F, Albayrak A, Boztok B, Delibasi T. Effect of stem cell application on Asherman syndrome, an experimental rat model. J Assist Reprod Genet 2014; 31(8): 975–982

[291] Su J, Ding L, Cheng J, Yang J, Li X, Yan G, Sun H, Dai J, Hu Y. Transplantation of adipose-derived stem cells combined with collagen scaffolds restores ovarian function in a rat model of premature ovarian insufficiency. Hum Reprod 2016; 31(5): 1075–1086

[292] Terraciano P, Garcez T, Ayres L, Durli I, Baggio M, Kuhl CP, Laurino C, Passos E, Paz AH, Cirne-Lima E. Cell therapy for chemically induced ovarian failure in mice. Stem Cells Int 2014; 2014: 720753

Acknowledgements

Authors express their gratitude and appreciation to all persons who contributed in this manuscript.

Compliance with ethics guidelines

Kosar Babaei, Mohsen Aziminezhad, Seyedeh Elham Norollahi, Sogand Vahidi, and Ali Akbar Samadani declare no conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2022 Higher Education Press