The Role of Epididymis and “Bio-Active Cargo” Exosome in Sperm Cells Maturation
DOI:
https://doi.org/10.46799/adv.v4i11.729Keywords:
epididymosomes, bio-active cargo, sperm cells, epididymisAbstract
Male infertility may result from impaired posttesticular sperm maturation, a process in which the epididymis provides a specialized luminal microenvironment essential for sperm development and functional competence. This narrative literature review examined the anatomical and physiological roles of the epididymis and the potential contributions of epididymosome-associated bioactive cargo to sperm maturation. Relevant literature published between 2015 and 2025 was identified through PubMed, ScienceDirect, and other scientific sources and synthesized according to epididymal structure, epithelial cell functions, extracellular vesicle biology, and the transfer of proteins and small regulatory RNAs. The reviewed evidence indicated that epididymosomes, a heterogeneous population of extracellular vesicles released into the epididymal lumen, participate in intercellular communication and may transfer bioactive molecules to spermatozoa during epididymal transit. These molecular interactions have been associated with sperm plasma membrane remodeling, acquisition of motility, protection against oxidative stress, and other posttesticular modifications essential for sperm functional maturation. Experimental studies further suggested that epididymosome-mediated cargo transfer contributes to molecular communication between the epididymal epithelium and developing spermatozoa. However, much of the mechanistic evidence was derived from animal models and in vitro experiments, limiting its direct applicability to human reproductive physiology. Furthermore, the clinical relevance of specific epididymosomal cargo molecules in human infertility remains insufficiently established. Overall, this review highlighted the potential of epididymosomes as sources of reproductive biomarkers and targets for future investigations rather than validated diagnostic or therapeutic tools. Further research should clarify cargo-specific mechanisms in humans and distinguish molecular changes acquired during epididymal maturation from those associated with subsequent sperm capacitation in the female reproductive tract.
References
Akmal, M., Masyitah, D., Hafizuddin, H., & Fitriani, F. (2015). Epididimis dan perannya pada pematangan spermatozoa. JESBIO: Jurnal Edukasi Dan Sains Biologi, 4(2).
Ali, W., Deng, K., Bian, Y., Liu, Z., & Zou, H. (2023). Spectacular role of epididymis and bio-active cargo of nano-scale exosome in sperm maturation: A review. Biomedicine & Pharmacotherapy, 164. https://doi.org/10.1016/j.biopha.2023.114889
Alzahrani, F. A., & Saadeldin, I. M. (2021). Role of Exosomes in Biological Communication Systems (1st ed.). Springer Singapore. https://doi.org/https://doi.org/10.1007/978-981-15-6599-1
Angrimani, D. S. R., Nichi, M., Losano, J. D. A., Lucio, C. F., Veiga, G. A. L., Franco, M. V. M. J., & Vannucchi, C. I. (2017). Fatty acid content in epididymal fluid and spermatozoa during sperm maturation in dogs. Journal of Animal Science and Biotechnology, 8(18). https://doi.org/https://doi.org/10.1186/s40104-017-0148-6
Barrachina, F., Battistone, M. A., Castillo, J., Mallofré, C., Jodar, M., Breton, S., & Oliva, R. (2022). Sperm acquire epididymis-derived proteins through epididymosomes. Human Reproduction, 37(4), 651–668. https://doi.org/10.1093/humrep/deac015
Devhare, P. B., & Ray, R. B. (2018). Extracellular vesicles: Novel mediator for cell to cell communications in liver pathogenesis. Molecular Aspects of Medicine, 60, 115–122. https://doi.org/10.1016/j.mam.2017.11.001
Diaz, P., Dullea, A., Chu, K., Zizzo, J., Loloi, J., & Reddy, R. (2022). Future of male infertility evaluation and treatment: brief review of Emerging Technology. Urology, 169, 9–16.
Dickhout, A., & Koenen, R. R. (2018). Extracellular Vesicles as Biomarkers in Cardiovascular Disease; Chances and Risks. Frontiers in Cardiovascular Medicine, 5. https://doi.org/10.3389/fcvm.2018.00113
Dunleavy, J. E. M., O’Bryan, M. K., Stanton, P. G., & O’Donnell, L. (2019). The cytoskeleton in spermatogenesis. Reproduction, 157(2), R53–R72. https://doi.org/10.1530/REP-18-0457
Eisenberg, M. L., Esteves, S. C., Lamb, D. J., Hotaling, J. M., Giwercman, A., Hwang, K., & Cheng, Y.-S. (2023). Male infertility. Nature Reviews Diseases Primers, 9(49). https://doi.org/https://doi.org/10.1038/s41572-023-00459-w
Faisal, K., & Akbarsha, M. A. (2021). Role of aposomes and epididymosomes in sperm quality control: A light and transmission electron microscopic study in an experimental rat model. Andrologia, 53(1), 1–9. https://doi.org/10.1111/and.13862
Foot, N. J., & Kumar, S. (2021). The Role of Extracellular Vesicles in Sperm Function and Male Fertility. New Frontiers: Extracellular Vesicles, 97. https://doi.org/https://doi.org/10.1007/978-3-030-67171-6_19
Frydrychowicz, M., Kolecka-Bednarczyk, A., Madejczyk, M., Yasar, S., & Dworacki, G. (2015). Exosomes - structure, biogenesis and biological role in non-small-cell lung cancer. Scandinavian Journal of Immunology, 81(1), 2–10. https://doi.org/10.1111/sji.12247
Gaikwad, A. S., Hu, J., Chapple, D. G., & Bryan, M. K. O. (2020). The functions of CAP superfamily proteins in mammalian fertility and disease. Human Reproduction Update, 26(5), 689–723. https://doi.org/10.1093/humupd/dmaa016
Griswold, M. D. (2016). Spermatogenesis: The commitment to Meiosis. Physiological Reviews, 96(1), 1–17. https://doi.org/10.1152/physrev.00013.2015
Hassan, F., & Holtz, W. (2024). Morphology of the epididymal duct of the domestic pig (Sus scrofa domesticus). Journal of Morphology, 285(2), 1–10. https://doi.org/10.1002/jmor.21675
Höög, J. L., & Lötvall, J. (2015). Diversity of extracellular vesicles in human ejaculates revealed by cryo-electron microscopy. Journal of Extracellular Vesicles, 4(1). https://doi.org/10.3402/jev.v4.28680
Huang, B., Wang, Z., Kong, Y., Jin, M., & Ma, L. (2023). Global, regional and national burden of male infertility in 204 countries and territories between 1990 and 2019: an analysis of global burden of disease study. BMC Public Health, 23(2195). https://doi.org/https://doi.org/10.1186/s12889-023-16793-3
Hutcheon, K., Mclaughlin, E. A., Stanger, S. J., Bernstein, I. R., Dun, M. D., Eamens, A. L., Nixon, B., Hutcheon, K., Mclaughlin, E. A., Stanger, S. J., Bernstein, I. R., Dun, M. D., Eamens, A. L., & Nixon, B. (2017). Analysis of the small non-protein-coding RNA profile of mouse spermatozoa reveals specific enrichment of piRNAs within mature spermatozoa. RNA Biology, 14(12), 1776–1790. https://doi.org/10.1080/15476286.2017.1356569
Ibtisham, F., Wu, J., Xiao, M., An, L., Banker, Z., Nawab, A., Zhao, Y., & Li, G. (2017). Progress and future prospect of in vitro spermatogenesis. Oncotarget, 8(39), 66709–66727. https://doi.org/10.18632/oncotarget.19640
James, E. R., Carrell, D. T., Aston, K. I., Jenkins, T. G., Yeste, M., & Salas-Huetos, A. (2020). The role of the epididymis and the contribution of epididymosomes to mammalian reproduction. International Journal of Molecular Sciences, 21(15), 1–17. https://doi.org/10.3390/ijms21155377
Kowalczyk, A., Wrzeci?ska, M., & Czerniawska-Pi?tkowska, Ewa Kupczy?ski, R. (2022). Exosomes – Spectacular role in reproduction. Biomedicine & Pharmacotherapy, 148. https://doi.org/10.1016/j.biopha.2022.112752
Kubota, H., & Brinster, R. L. (2018). Spermatogonial stem cells. Biology of Reproduction, 99(1), 52–74. https://doi.org/10.1093/biolre/ioy077
Leir, S. H., Yin, S., Kerschner, J. L., Cosme, W., & Harris, A. (2020). An atlas of human proximal epididymis reveals cell-specific functions and distinct roles for CFTR. Life Science Alliance, 3(11), 1–15. https://doi.org/10.26508/LSA.202000744
Liu, M. M., Feng, X. L., Qi, C., Zhang, S. E., & Zhang, G. L. (2024). The significance of single-cell transcriptome analysis in epididymis research. Frontiers in Cell and Developmental Biology, 12(March), 1–12. https://doi.org/10.3389/fcell.2024.1357370
Machtinger, R., Laurent, L. C., & Baccarelli, A. A. (2016). Extracellular vesicles: Roles in gamete maturation, fertilization and embryo implantation. Human Reproduction Update, 22(2), 182–193. https://doi.org/10.1093/humupd/dmv055
Martin-Deleon, P. A. (2015). Epididymosomes: Transfer of fertility-modulating proteins to the sperm surface. Asian Journal of Andrology, 17(5), 720–725. https://doi.org/10.4103/1008-682X.155538
Martínez-Martínez, N., Martínez-Alonso, E., Tomás, M., Neumüller, J., Pavelka, M., & Martínez-Menárguez, J. A. (2017). A new insight into the three-dimensional architecture of the Golgi complex: Characterization of unusual structures in epididymal principal cells. PLoS ONE, 12(9), 1–23. https://doi.org/10.1371/journal.pone.0185557
Méar, L. O., Tsai, P.-S., Tamessar, C. T., Schjenken, J. E., & Nixon, B. (2024). Epididymosomes: Composition and Functions for Sperm Maturation. In Advances in Anatomy, Embryology and Cell Biology (pp. 1–16). Springer. https://doi.org/https://doi.org/10.1007/102_2024_7
Nixon, B., De Iuliis, G. N., Hart, H. M., Zhou, W., Mathe, A., Bernstein, I. R., Anderson, A. L., Stanger, S. J., Skerrett-Byrne, D. A., Fairuz Jamaluddin, M. B., Almazi, J. G., Bromfield, E. G., Larsen, M. R., & Dun, M. D. (2019). Proteomic profiling of mouse epididymosomes reveals their contributions to post-testicular sperm maturation. Molecular and Cellular Proteomics, 18(March), S91–S108. https://doi.org/10.1074/mcp.RA118.000946
O’Brien, K., Breyne, K., Ughetto, S., Laurent, L. C., & Breakefield, X. O. (2020). RNA delivery by extracellular vesicles in mammalian cells and its applications. Nature Reviews Molecular Cell Biology, 21, 585–606. https://doi.org/10.1038/s41580-020-0251-y
Reilly, J. J. (2016). When does it all go wrong? Longitudinal studies of changes in moderate-to-vigorous-intensity physical activity across childhood and adolescence. Journal of Exercise Science and Fitness, 14(1), 1–6. https://doi.org/10.1016/j.jesf.2016.05.002
Rompala, G. R., Mounier, A., Wolfe, C. M., Lin, Q., Lefterov, I., & Homanics, G. E. (2018). Heavy chronic intermittent ethanol exposure alters small noncoding RNAs in mouse sperm and epididymosomes. Frontiers in Genetics, 9(FEB). https://doi.org/10.3389/fgene.2018.00032
Sharma, R., Sharma, P., Katiyar, V., Vora, Z., & Gurjar, H. (2018). Hyponatremia Following Aneurysmal Subarachnoid Hemorrhage. World Neurosurgery, 115, 481. https://doi.org/10.1016/j.wneu.2018.02.197
Sharma, U., Conine, C. C., Shea, J. M., Boskovie, A., Derr, A. G., Bing, X. Y., Belleannee, C., Kucukural, A., Serra, R. W., Sun, F., Song, L., Carone, B. R., Ricci, E. P., Li, X. Z., Fauquier, L., Moore, M. J., Sullivan, R., Mello, C. C., Garber, M., & Rando, O. J. (2016). Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals (Vol. 351, Issue 6271). https://doi.org/10.1126/science.aad6780
Stahl, P. D., & Raposo, G. (2019). Extracellular Vesicles: Exosomes and Microvesicles, Integrators of Homeostasis. Physiology, 34(3), 169–177. https://doi.org/10.1152/physiol.00045.2018
Tarique, I., Haseeb, A., Bai, X., Li, W., Yang, P., Huang, Y., Yang, S., Xu, M., Zhang, Y., Vistro, W. A., Fazlani, S. A., & Chen, Q. (2019). Cellular Evidence of CD63-Enriched Exosomes and Multivesicular Bodies within the Seminiferous Tubule during the Spermatogenesis of Turtles. Microscopy and Microanalysis, 26(1), 148–156. https://doi.org/10.1017/S1431927619015149
Teves, M. E., & Roldan, E. R. S. (2022). Spermbauplan and function and underlying processes of sperm formation and selection. Physiological Reviews, 102(1), 7–60. https://doi.org/10.1152/PHYSREV.00009.2020
Vander Borght, M., & Wyns, C. (2018). Fertility and infertility: Definition and epidemiology. Clinical Biochemistry, 62(February), 2–10. https://doi.org/10.1016/j.clinbiochem.2018.03.012
Vistro, W. A., Huang, Y., Bai, X., Yang, P., Haseeb, A., Chen, H., Liu, Y., Yue, Z., Tarique, I., & Chen, Q. (2019). In Vivo Multivesicular Body and Exosome Secretion in the Intestinal Epithelial Cells of Turtles During Hibernation. Microscopy and Microanalysis, 25(6), 1341–1351. https://doi.org/10.1017/S1431927619015071
World Health Organization. (2023). Infertility. https://www.who.int/news-room/fact-sheets/detail/infertility
Wu, F. J., Lin, T. Y., Sung, L. Y., Chang, W. F., Wu, P. C., & Luo, C. W. (2017). BMP8A sustains spermatogenesis by activating both SMAD1/5/8 and SMAD2/3 in spermatogonia. Science Signaling, 10(477), 1–14. https://doi.org/10.1126/scisignal.aal1910
Yoshida, S. (2019). Heterogeneous, dynamic, and stochastic nature of mammalian spermatogenic stem cells. In Current Topics in Developmental Biology (1st ed., Vol. 135). Elsevier Inc. https://doi.org/10.1016/bs.ctdb.2019.04.008
Zhang, X., Zheng, R., Liang, C., Liu, H., Zhang, X., Ma, Y., Liu, M., Zhang, W., Yang, Y., Liu, M., Jiang, C., Ren, Q., Wang, Y., Chen, S., Yang, Y., & Shen, Y. (2022). Loss-of-function mutations in CEP78 cause male infertility in humans and mice. Science Advances, 8(40), 1–18. https://doi.org/10.1126/sciadv.abn0968
Zhao, H., Yu, C., He, C., Mei, C., Liao, A., & Huang, D. (2020). The Immune Characteristics of the Epididymis and the Immune Pathway of the Epididymitis Caused by Different Pathogens. Frontiers in Immunology, 11(September), 1–12. https://doi.org/10.3389/fimmu.2020.02115
Zhou, W., De Iuliis, G. N., Dun, M. D., & Nixon, B. (2018). Characteristics of the epididymal luminal environment responsible for sperm maturation and storage. Frontiers in Endocrinology, 9(FEB), 1–13. https://doi.org/10.3389/fendo.2018.00059
