Research Article

The Effects of Human Umbilical Cord Mesenchymal Stem Cell Transplantation on Female Fertility Restoration in Mice

Author(s): Qiwei Liu, Junhui Zhang*, Yong Tang, Yuanyuan Ma, Zhigang Xue and Jinjuan Wang*

Volume 22, Issue 4, 2022

Published on: 26 November, 2021

Page: [319 - 330] Pages: 12

DOI: 10.2174/1566523221666211014165341

Price: $65

Abstract

Background: Female fertility refers to the capacity to produce oocytes and achieve fertilization and pregnancy, and it is impaired by age, disease, environment and social pressure. However, no effective therapy that restores female reproductive ability has been established. Mesenchymal Stromal Cells (MSCs) exhibit multilineage differentiation potential and have attracted considerable attention as a tool for restoring female fertility.

Methods: This study used human umbilical cord-MSCs (Huc-MSCs) to restore fertility in aging female mice and mice with chemotherapy-induced damage through the rescue of ovarian function and reconstruction of the fallopian tubes and uterus. In our study, two mouse models were generated: aging mice (35 weeks of age) and mice with chemotherapy-induced damage.

Results: The effect of MSCs on the ovaries, fallopian tubes and uterus was evaluated by analyzing gonadal hormone levels and by performing morphological and statistical analyses. The levels of estradiol (E2) and follicle-stimulating hormone (FSH) exhibited significant recovery after Huc-MSC transplantation in both aging mice and chemotherapy-treated mice. Huc-MSC treatment also increased the number of primordial, developing and preovulatory follicles in the ovaries of mice. Moreover, MSCs were shown to rescue the morphology of the fallopian tubes and uterus through mechanisms such as cilia regeneration in the fallopian tubes and reformation of glands and endometrial tissue in the uterus.

Conclusion: Huc-MSCs may represent an effective treatment for restoring female fertility through recovery from chemotherapy-induced damage and rescue of female reproductive organs from the effects of aging.

Keywords: Female reproduction, MSCs, aging, chemotherapy, mice, mesenchymal stromal cells (MSCs).

Graphical Abstract
[1]
Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2008; 2(4): 313-9.
[http://dx.doi.org/10.1016/j.stem.2008.03.002] [PMID: 18397751]
[2]
Bleyer A, Viny A, Barr R. Cancer in 15- to 29-year-olds by primary site. Oncologist 2006; 11(6): 590-601.
[http://dx.doi.org/10.1634/theoncologist.11-6-590] [PMID: 16794238]
[3]
Brice P, Haioun C, André M, Gisselbrecht C. Pregnancies after high-dose chemotherapy and autologous stem cell transplantation in aggressive lymphomas. Blood 2002; 100(2): 736.
[http://dx.doi.org/10.1182/blood.V100.2.736] [PMID: 12123236]
[4]
Briceag I, Costache A, Purcarea VL, et al. Fallopian tubes-literature review of anatomy and etiology in female infertility. J Med Life 2015; 8(2): 129-31.
[PMID: 25866566]
[5]
Critchley HO, Bath LE, Wallace WH. Radiation damage to the uterus - review of the effects of treatment of childhood cancer. Hum Fertil (Camb) 2002; 5(2): 61-6.
[http://dx.doi.org/10.1080/1464727022000198942] [PMID: 12082209]
[6]
El Omar R, Beroud J, Stoltz JF, Menu P, Velot E, Decot V. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? Tissue Eng Part B Rev 2014; 20(5): 523-44.
[http://dx.doi.org/10.1089/ten.teb.2013.0664] [PMID: 24552279]
[7]
Garcia-Velasco JA, Domingo J, Cobo A, Martínez M, Carmona L, Pellicer A. Five years’ experience using oocyte vitrification to preserve fertility for medical and nonmedical indications. Fertil Steril 2013; 99(7): 1994-9.
[http://dx.doi.org/10.1016/j.fertnstert.2013.02.004] [PMID: 23465707]
[8]
Gumułka M, Kapkowska E. Age effect of broiler breeders on fertility and sperm penetration of the perivitelline layer of the ovum. Anim Reprod Sci 2005; 90(1-2): 135-48.
[http://dx.doi.org/10.1016/j.anireprosci.2005.01.018] [PMID: 16257603]
[9]
Gutiérrez-Fernández M, Rodríguez-Frutos B, Ramos-Cejudo J, et al. Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Res Ther 2013; 4(1): 11.
[http://dx.doi.org/10.1186/scrt159] [PMID: 23356495]
[10]
Islam MR, Yamagami K, Yoshii Y, Yamauchi N. Growth factor induced proliferation, migration, and lumen formation of rat endometrial epithelial cells in vitro. J Reprod Dev 2016; 62(3): 271-8.
[http://dx.doi.org/10.1262/jrd.2015-158] [PMID: 26946922]
[11]
Jin HJ, Kwon JH, Kim M, et al. Downregulation of melanoma cell adhesion molecule (MCAM/CD146) accelerates cellular senescence in human umbilical cord blood-derived mesenchymal stem cells. Stem Cells Transl Med 2016; 5(4): 427-39.
[http://dx.doi.org/10.5966/sctm.2015-0109] [PMID: 26941359]
[12]
Liu S, Liu F, Zhou Y, Jin B, Sun Q, Guo S. Immunosuppressive property of MSCs mediated by cell surface receptors. Front Immunol 2020; 11: 1076.
[http://dx.doi.org/10.3389/fimmu.2020.01076] [PMID: 32849489]
[13]
Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005; 122(2): 303-15.
[http://dx.doi.org/10.1016/j.cell.2005.06.031] [PMID: 16051153]
[14]
Kadam P, Ntemou E, Onofre J, Van Saen D, Goossens E. Does co-transplantation of mesenchymal and spermatogonial stem cells improve reproductive efficiency and safety in mice? Stem Cell Res Ther 2019; 10(1): 310.
[http://dx.doi.org/10.1186/s13287-019-1420-9] [PMID: 31640769]
[15]
Lai D, Wang F, Yao X, Zhang Q, Wu X, Xiang C. Human endometrial mesenchymal stem cells restore ovarian function through improving the renewal of germline stem cells in a mouse model of premature ovarian failure. J Transl Med 2015; 13: 155.
[http://dx.doi.org/10.1186/s12967-015-0516-y] [PMID: 25964118]
[16]
Li Z, Zhang Z, Chen X, Zhou J, Xiao XM. Treatment evaluation of Wharton’s jelly-derived mesenchymal stem cells using a chronic salpingitis model: an animal experiment. Stem Cell Res Ther 2017; 8(1): 232.
[http://dx.doi.org/10.1186/s13287-017-0685-0] [PMID: 29041961]
[17]
Liao W, Tang X, Li X, Li T. Therapeutic effect of human umbilical cord mesenchymal stem cells on tubal factor infertility using a chronic salpingitis murine model. Arch Gynecol Obstet 2019; 300(2): 421-9.
[http://dx.doi.org/10.1007/s00404-019-05209-6] [PMID: 31190174]
[18]
Liu F, Hu S, Yang H, et al. 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.
[http://dx.doi.org/10.1002/adhm.201900411] [PMID: 31148407]
[19]
Maheshwari A, Hamilton M, Bhattacharya S. Effect of female age on the diagnostic categories of infertility. Hum Reprod 2008; 23(3): 538-42.
[http://dx.doi.org/10.1093/humrep/dem431] [PMID: 18308834]
[20]
May-Panloup P, Boucret L, Chao de la Barca JM, et al. Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum Reprod Update 2016; 22(6): 725-43.
[http://dx.doi.org/10.1093/humupd/dmw028] [PMID: 27562289]
[21]
Mohamed Y, Basyony MA, El-Desouki NI, Abdo WS, El-Magd MA. The potential therapeutic effect for melatonin and mesenchymal stem cells on hepatocellular carcinoma. Biomedicine (Taipei) 2019; 9(4): 24.
[http://dx.doi.org/10.1051/bmdcn/2019090424] [PMID: 31724939]
[22]
Rangappa S, Entwistle JW, Wechsler AS, Kresh JY. Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype. J Thorac Cardiovasc Surg 2003; 126(1): 124-32.
[http://dx.doi.org/10.1016/S0022-5223(03)00074-6] [PMID: 12878947]
[23]
Regmi S, Pathak S, Kim JO, Yong CS, Jeong JH. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol 2019; 98(5-8): 151041.
[http://dx.doi.org/10.1016/j.ejcb.2019.04.002] [PMID: 31023504]
[24]
Rivkees SA, Crawford JD. The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA 1988; 259(14): 2123-5.
[http://dx.doi.org/10.1001/jama.1988.03720140043031] [PMID: 3162285]
[25]
Roness H, Kalich-Philosoph L, Meirow D. Prevention of chemotherapy-induced ovarian damage: possible roles for hormonal and non-hormonal attenuating agents. Hum Reprod Update 2014; 20(5): 759-74.
[http://dx.doi.org/10.1093/humupd/dmu019] [PMID: 24833728]
[26]
Shin TH, Lee BC, Choi SW, et al. Human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis via regulation of B lymphocyte maturation. Oncotarget 2017; 8(1): 512-22.
[http://dx.doi.org/10.18632/oncotarget.13473] [PMID: 27888809]
[27]
Silvestris E, Lovero D, Palmirotta R. Nutrition and female fertility: an interdependent correlation. Front Endocrinol (Lausanne) 2019; 10: 346.
[http://dx.doi.org/10.3389/fendo.2019.00346] [PMID: 31231310]
[28]
Song D, Zhong Y, Qian C, et al. Human umbilical cord mesenchymal stem cells therapy in cyclophosphamide-induced premature ovarian failure rat model. BioMed Res Int 2016; 2016: 2517514.
[http://dx.doi.org/10.1155/2016/2517514] [PMID: 27047962]
[29]
Staal FJ, Baum C, Cowan C, et al. Stem cell self-renewal: lessons from bone marrow, gut and iPS toward clinical applications. Leukemia 2011; 25(7): 1095-102.
[http://dx.doi.org/10.1038/leu.2011.52] [PMID: 21527933]
[30]
Vollenhoven B, Hunt S. Ovarian ageing and the impact on female fertility. F1000 Res 2018; 7: 7.
[http://dx.doi.org/10.12688/f1000research.16509.1] [PMID: 30542611]
[31]
Zhang H, Luo Q, Lu X, et al. Effects of hPMSCs on granulosa cell apoptosis and AMH expression and their role in the restoration of ovary function in premature ovarian failure mice. Stem Cell Res Ther 2018; 9(1): 20.
[http://dx.doi.org/10.1186/s13287-017-0745-5] [PMID: 29386068]
[32]
Woods L, Perez-Garcia V, Kieckbusch J, et al. Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nat Commun 2017; 8(1): 352.
[http://dx.doi.org/10.1038/s41467-017-00308-x] [PMID: 28874785]
[33]
Xiao GY, Liu IH, Cheng CC, et al. 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.
[http://dx.doi.org/10.1371/journal.pone.0106538] [PMID: 25198549]
[34]
Yang K, Park HJ, Han S, et al. Recapitulation of in vivo-like paracrine signals of human mesenchymal stem cells for functional neuronal differentiation of human neural stem cells in a 3D microfluidic system. Biomaterials 2015; 63: 177-88.
[http://dx.doi.org/10.1016/j.biomaterials.2015.06.011] [PMID: 26113074]
[35]
Yang Z, Du X, Wang C, et al. 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.
[http://dx.doi.org/10.1186/s13287-019-1327-5] [PMID: 31412919]
[36]
Zhou X, Hong Y, Zhang H, Li X. Mesenchymal stem cell senescence and rejuvenation: current status and challenges. Front Cell Dev Biol 2020; 8: 364.
[http://dx.doi.org/10.3389/fcell.2020.00364] [PMID: 32582691]
[37]
Zhang Y, Lin X, Dai Y, et al. Endometrial stem cells repair injured endometrium and induce angiogenesis via AKT and ERK pathways. Reproduction 2016; 152(5): 389-402.
[http://dx.doi.org/10.1530/REP-16-0286] [PMID: 27486270]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy