The role of stem cell-based extracellular vesicles in male fertility

Abstract

Fertility tends to decrease over time in physiological or various pathological conditions. Preservation of male and female fertility is of equal importance for successful reproduction. Protection and maintenance of male fertility and infertility treatment are among the medical fields that have attracted attention, especially in recent years. Various therapeutic approaches, especially sperm and testicular tissue cryopreservation, are applied for the preservation and continuity of fertility. In addition to these methods, which are routinely used, there is an increasing interest in stem cell-based therapies, which are not only aimed at preserving fertility but also effective in infertility treatment. Stem cells are therapeutic agents with high differentiation potential found at every stage of life. In the light of the studies, it has been determined that besides all the positive effects of stem cells, they contain nanoparticles known as extracellular vesicles in their structures. This review will discuss the type of extracellular vesicles, their biological functions, the use of stem cell-based extracellular vesicles in men, and current studies.

Keywords

• fertility
• stem cells
• extracellular vesicles
• exosome

References

1. 1. Hu H, Ji G, Shi X, Zhang J, Li M. Current Status of Male Fertility Preservation in Humans. Russian Journal of Developmental Biology. 2022; 53(2): 134-140.
2. 2. Picton HM, Wyns C, Anderson RA, Goossens E, Jahnukainen K, Kliesch S, et al. A European perspective on testicular tissue cryopreservation for fertility preservation in prepubertal and adolescent boys. Human reproduction. 2015; 30(11): 2463-2475.
3. 3. Kharazi U, Badalzadeh R. A review on the stem cell therapy and an introduction to exosomes as a new tool in reproductive medicine. Reproductive Biology. 2020; 20(4): 447-459.
4. 4. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006; 20: 847–856.
5. 5. Klymiuk MC, Balz N, Elashry MI, Heimann M, Wenisch S, Arnhold S. Exosomes isolation and identification from equine mesenchymal stem cells. BMC Veterinary Research. 2019; 15(1): 1-9.
6. 6. Deatherage BL, Cookson BT. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infection and immunity. 2012; 80(6): 1948-1957.
7. 7. D'Souza-Schorey C, Clancy JW. Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes & development. 2012; 26(12): 1287-1299.
8. 8. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. 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. Journal of extracellular vesicles. 2018; 7(1): 1535750.

9. 9. Yáñez-Mó M, Siljander PRM, Andreu Z, Bedina Zavec A, Borràs FE, Buzas EI, et al. Biological properties of extracellular vesicles and their physiological functions. Journal of extracellular vesicles. 2015; 4(1): 27066.
10. 10. Margolis L, Sadovsky Y. (2019). The biology of extracellular vesicles: The known unknowns. PLoS biology. 2019; 17(7): e3000363.
11. 11. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. Journal of Cell Biology. 2013; 200(4): 373-383.
12. 12. Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current protocols in cell biology. 2006; 30(1): 3-22.
13. 13. Keller S, Ridinger J, Rupp AK, Janssen JW, Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics. Journal of translational medicine. 2011; 9(1): 1-9.
14. 14. Konala VBR, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy. 2016; 18(1): 13-24.
15. 15. Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischemia-reperfusion-induced acute and chronic kidney injury. Nephrology Dialysis Transplantation. 2011; 26: 1474–1483.
16. 16. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief C, et al. B lymphocytes secrete antigen-presenting vesicles. The Journal of Experimental Meidicine. 1996; 183: 1161–1172.
17. 17. El Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nature reviews Drug discovery. 2013; 12(5): 347-357.
18. 18. 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 Communication and Signaling. 2014; 12(1): 1-12.
19. 19. Pascucci L, Alessandri G, Dall'Aglio C, Mercati F, Coliolo P, Bazzucchi C, et al. Membrane vesicles mediate pro-angiogenic activity of equine adipose-derived mesenchymal stromal cells. The Veterinary Journal. 2014; 202(2): 361-366.
20. 20. Machtinger R, Laurent LC, Baccarelli AA. Extracellular vesicles: roles in gamete maturation, fertilization, and embryo implantation. Human reproduction update. 2016; 22(2): 182-193.
21. 21. Nawaz M, Camussi G, Valadi H, Nazarenko I, Ekström K, Wang X, et al. The emerging role of extracellular vesicles as biomarkers for urogenital cancers. Nature Reviews Urology. 2014; 11(12): 688-701.
22. 22. Konoshenko MY, Lekchnov EA, Vlassov AV, Laktionov PP. Isolation of extracellular vesicles: general methodologies and latest trends. BioMed research international. 2018.
23. 23. Li P, Kaslan M, Lee SH, Yao J, Gao Z. Progress in exosome isolation techniques. Theranostics. 2017; 7(3): 789.
24. 24. McVey M, Tabuchi A, Kuebler WM. Microparticles and acute lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2012; 303(5): L364-L381.
25. 25. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. Journal of proteomics. 2010; 73(10): 1907-1920.
26. 26. Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. Journal of lipid research. 2010; 51(8): 2105-2120.
27. 27. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer and Metastasis Reviews. 2013; 32(3): 623-642.
28. 28. Kim WS, Park BS, Sung JH, Yang JM, Park SB, Kwak SJ, et al. Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. Journal of dermatological science. 2007; 48(1): 15-24.
29. 29. Kostereva N, Hofmann MC. Regulation of the spermatogonial stem cell niche. Reproduction in Domestic Animals. 2008; 43: 386-392.
30. 30. Qamar AY, Fang X, Kim MJ, Cho J. Improved viability and fertility of frozen-thawed dog sperm using adipose-derived mesenchymal stem cells. Scientific reports. 2020; 10(1): 1-10.
31. 31. Griffiths GS, Galileo DS, Reese K, Martin‐DeLeon PA. Investigating the role of murine epididymosomes and uterosomes in GPI‐linked protein transfer to sperm using SPAM1 as a model. Molecular Reproduction and Development: Incorporating Gamete Research. 2008; 75(11): 1627-1636.
32. 32. Sullivan R, Saez F. Epididymosomes, prostasomes, and liposomes: their roles in mammalian male reproductive physiology. Reproduction. 2013; 146(1): R21-R35.
33. 33. Ronquist G, Brody I. The prostasome: its secretion and function in man. Biochimica et Biophysica Acta (BBA)-Reviews on Biomembranes. 1985; 822(2): 203-218.
34. 34. Pons‐Rejraji H, Artonne C, Sion B, Brugnon F, Canis M, Janny L, et al. Prostasomes: inhibitors of capacitation and modulators of cellular signalling in human sperm. International journal of andrology. 2011; 34(6pt1): 568-580.
35. 35. Saez F, Motta C, Boucher D, Grizard G. Antioxidant capacity of prostasomes in human semen. Molecular human reproduction. 1998; 4(7): 667-672.
36. 36. Carlsson L, Påhlson C, Bergquist M, Ronquist G, Stridsberg M. Antibacterial activity of human prostasomes. The Prostate. 2000; 44(4): 279-286.
37. 37. Mourvaki E, Cardinali R, Dal Bosco A, Castellini C. In vitro antioxidant activity of the prostatic secretory granules in rabbit semen after exposure to organic peroxides. Reproductive Biology and Endocrinology. 2010; 8(1): 1-7.
38. 38. Alberts M, van Dissel-Emiliani FM, van Adrichem NP, van Wijnen M, Wauben MH., Stout TA, et al. Identification of distinct populations of prostasomes that differentially express prostate stem cell antigen, annexin A1, and GLIPR2 in humans. Biology of reproduction. 2012; 86(3): 82-1.
39. 39. Frenette G, Lessard C, Madore E, Fortier MA, Sullivan R. Aldose reductase and macrophage migration inhibitory factor are associated with epididymosomes and spermatozoa in the bovine epididymis. Biology of reproduction. 2003; 69(5): 1586-1592.
40. 40. Tamessar CT, Trigg NA, Nixon B, Skerrett‐Byrne DA, Sharkey DJ, Robertson SA, et al. Roles of male reproductive tract extracellular vesicles in reproduction. American Journal of Reproductive Immunology. 2021; 85(2): e13338.
41. 41. Belleannee C, Legare C, Calvo E, Thimon V, Sullivan R. microRNA signature is altered in both human epididymis and seminal microvesicles following vasectomy. Human reproduction. 2013; 28(6): 1455-1467.
42. 42. Murdica V, Giacomini E, Alteri A, Bartolacci A, Cermisoni GC, Zarovni N, et al. Seminal plasma of men with severe asthenozoospermia contain exosomes that affect spermatozoa motility and capacitation. Fertility and Sterility. 2019; 111(5): 897-908.
43. 43. Carlini E, Palmerini CA, Cosmi EV, Arienti G. Fusion of sperm with prostasomes: effects on membrane fluidity. Archives of biochemistry and biophysics. 1997; 343(1): 6-12.
44. 44. Siciliano L, Marcianò V, Carpino A. Prostasome-like vesicles stimulate acrosome reaction of pig spermatozoa. Reproductive Biology and Endocrinology. 2008; 6(1): 1-7.
45. 45. Bianchi E, Wright GJ. Izumo meets Juno: preventing polyspermy in fertilization. Cell cycle. 2014; 13(13): 2019-2020.
46. 46. Mokarizadeh A, Rezvanfar MA, Dorostkar K, Abdollahi M. Mesenchymal stem cell-derived microvesicles: trophic shuttles for enhancement of sperm quality parameters. Reproductive Toxicology. 2013; 42: 78-84.
47. 47. Qamar AY, Fang X, Kim MJ, Cho J. Improved post-thaw quality of canine semen after treatment with exosomes from conditioned medium of adipose-derived mesenchymal stem cells. Animals. 2019; 9(11): 865.
48. 48. Rowlison T, Ottinger MA, Comizzoli P. Exposure to epididymal extracellular vesicles enhances immature sperm function and sustains vitality of cryopreserved spermatozoa in the domestic cat model. Journal of Assisted Reproduction and Genetics. 2021; 38(8): 2061-2071.
49. 49. Mahdavinezhad F, Gilani MAS, Gharaei R, Ashrafnezhad Z, Valipour J, Nashtai MS, et al. Protective roles of seminal plasma exosomes and microvesicles during human sperm cryopreservation. Reproductive BioMedicine Online. 2022
50. 50. Park KH, Kim BJ, Kang J, Nam TS, Lim JM, Kim HT, et al. Ca2+ signaling tools acquired from prostasomes are required for progesterone-induced sperm motility. Science signaling. 2011; 4(173): ra31-ra31.
51. 51. Du J, Shen J, Wang Y, Pan C, Pang W, Diao H, et al. Boar seminal plasma exosomes maintain sperm function by infiltrating into the sperm membrane. Oncotarget. 2016; 7(37): 58832.
52. 52. Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. British journal of cancer. 2009; 100(10): 1603-1607.
53. 53. Riazifar M, Pone EJ, Lötvall J, Zhao W. Stem cell extracellular vesicles: extended messages of regeneration. Annual review of pharmacology and toxicology. 2017; 57: 125-154.
54. 54. Zhang L, Wrana JL. The emerging role of exosomes in Wnt secretion and transport. Current opinion in genetics & development. 2014; 27: 14-19.
55. 55. Clevers H, Loh KM, Nusse R. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014; 346(6205): 1248012.
56. 56. Gomzikova MO, Rizvanov AA. Current trends in regenerative medicine: from cell to cell-free therapy. Bionanoscience. 2017; 7(1): 240-245.
57. 57. Gauthier‐Fisher A, Kauffman A, Librach CL. Potential use of stem cells for fertility preservation. Andrology. 2020; 8(4): 862-878.
58. 58. Lai RC, Yeo RWY, Tan SS, Zhang B, Yin Y, Sze NSK, et al. Mesenchymal stem cell exosomes: the future MSC-based therapy?. In Mesenchymal stem cell therapy. Humana Press, Totowa, NJ. 2013; 39-61.
59. 59. Basu J, Ludlow JW. Exosomes for repair, regeneration, and rejuvenation. Expert Opinion on Biological Therapy. 2016; 16(4): 489-506.
60. 60. de Bakker E, Van Ryssen B, De Schauwer C, Meyer E. Canine mesenchymal stem cells: state of the art, perspectives as therapy for dogs and as a model for man. Veterinary Quarterly. 2013; 33(4): 225-233.
61. 61. Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem cells. 2006; 24(5): 1294-1301.
62. 62. Rogers CJ, Harman RJ, Bunnell BA, Schreiber MA, Xiang C, Wang FS, et al. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. Journal of translational medicine. 2020; 18: 1-19.
63. 63. Mahiddine FY, Qamar AY, Kim M J. Canine amniotic membrane-derived mesenchymal stem cells exosomes addition in canine sperm freezing medium. Journal of Animal Reproduction and Biotechnology. 2020; 35(3): 268-272.
64. 64. Zhu LL, Huang X, Yu W, Chen H, Chen Y, Dai YT. Transplantation of adipose tissue‐derived stem cell‐derived exosomes ameliorates erectile function in diabetic rats. Andrologia. 2018; 50(2): e12871.
65. 65. Chen F, Zhang H, Wang Z, Ding W, Zeng Q, Liu W, et al. Adipose-derived stem cell-derived exosomes ameliorate erectile dysfunction in a rat model of type 2 diabetes. The journal of sexual medicine. 2017; 14(9): 1084-1094.
66. 66. De Rooıj DG, Russell LD. All you wanted to know about spermatogonia but were afraid to ask. Journal of andrology. 2000; 21(6): 776-798.
67. 67. Kanatsu-Shinohara M, Shinohara T. Spermatogonial stem cell self-renewal and development. Annual review of cell and developmental biology. 2013; 29: 163-187.
68. 68. Li Q, Li H, Liang J, Mei J, Cao Z, Zhang L, et al. Sertoli cell‐derived exosomal MicroRNA‐486‐5p regulates differentiation of spermatogonial stem cell through PTEN in mice. Journal of cellular and molecular medicine. 2021; 25(8): 3950-3962.
69. 69. Lin Y, Fang Q, He Y, Gong X, Wang Y, Liang A, et al. Thy1-positive spermatogonia suppress the proliferation of spermatogonial stem cells by Extracellular vesicles in vitro. Endocrinology. 2021; 162(7): bqab052.