Extracellular Vesicles Present in Bone Marrow Mesenchymal Stromal/Stem Cell Conditioned Media Restore Spermatogenesis in Azoospermic Mice
Zhankina R. Zare A. Afshar A. Khoradmehr A. Dorvash M.R. Rahmanifar F. Tanideh N. Hosseinabadi O.K. Monfared A.A. Zare S. Mussin N.M. Kaliyev A.A. Zhanbyrbekuly U. Tamadon A.
July 2025Royan Institute (ACECR)
International Journal of Fertility and Sterility
2025#19Issue 3305 - 318 pp.
Background: We aimed to examine the therapeutic efficacy of exosome-enriched conditioned media (CM), known for its high concentration of extracellular vesicles (EVs), in comparision with mesenchymal stromal/stem cells (MSCs) in treating non-obstructive azoospermia. Materials and Methods: In this experimental study, we used adipose tissue-derived MSCs (AT-MSCs), bone marrow-derived MSCs (BM-MSCs), and BMCM containing EVs to treat busulfan-induced azoospermia in animal models. The study included thirty adult male Balb/C mice and two female enhanced green fluorescent protein-positive (eGFP+/+) Balb/C mice for experimental groups and stem cell culturing. Groups consisted of an intact control, an azoospermia group, an AT-MSC therapy group, a BM-MSC therapy group, a BMCM therapy group, and a spontaneous healing group. Testes were removed from all mice, and histomorphometry and flow cytometry analyses were performed 60 days post-treatment. Additionally, protein structure extraction, protein-protein docking analysis, and data visualization were conducted. Results: Histomorphometry and flow cytometry showed that most seminiferous tubules in the therapy groups exhibited normal morphology and restored spermatogenesis, unlike the azoospermia group. In silico protein docking analysis revealed that exosome factors in BM-MSCs positively impacted spermatogenesis. The BM-MSC and BMCM therapy groups showed more favorable outcomes compared to other groups. Key exosome factors like Basigin, E3 ubiquitinprotein ligase (UBR2), transforming growth factor beta (TGF-β), hepatocyte growth factor (HGF), and programmed death-ligand 1 (PD-L1) interacted with receptors critical to this process. Conclusion: Our findings indicate that both BMCM enriched with EVs and the administration of AT-MSCs and BM-MSCs effectively induced spermatogenesis in mice with busulfan-induced azoospermia. Specifically, BM-MSC therapy exhibited superior outcomes compared to AT-MSCs and BMCM alone. This study highlights the potential of EV-based therapies, particularly BMCM, as a promising strategy for treating non-obstructive azoospermia. Furthermore, the interaction of key exosome factors with critical receptors enhances our understanding of the underlying molecular mechanisms involved in restoring reproductive function in testes.
Azoospermia , Extracellular Vesicles , Mesenchymal Stromal/Stem Cell
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Department of Urology and Andrology, Astana Medical University, Astana, Kazakhstan
PerciaVista R&D Co., Shiraz, Iran
Student Research Committee, Bushehr University of Medical Sciences, Bushehr, Iran
The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
Department of Pharmacology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
Central Lab, Shiraz University of Medical Sciences, Shiraz, Iran
West-Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
Department of Natural Sciences, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
Department of Urology and Andrology
PerciaVista R&D Co.
Student Research Committee
The Persian Gulf Marine Biotechnology Research Center
Stem Cells Technology Research Center
Department of Basic Sciences
Department of Pharmacology
Central Lab
West-Kazakhstan Marat Ospanov Medical University
Department of Natural Sciences
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