Improving Fertility in Non-obstructive Azoospermia: Results from an Autologous Bone Mar-row-Derived Mesenchymal Stromal/Stem Cell Phase I Clinical Trial

Background: In this phase I clinical trial, our primary objective was to develop an innovative therapeutic approachutilizing autologous bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs) for the treatment of nonobstructiveazoospermia (NOA). Additionally, we aimed to assess the feasibility and safety of this approach. Materials and Methods: We recruited 80 participants in this non-randomized, open-label clinical trial, including patientsundergoing NOA treatment using autologous BM-MSCs (n=40) and those receiving hormone therapy as a control group(n=40). Detailed participant characteristics, such as age, baseline hormonal profiles, etiology of NOA, and medical history,were thoroughly documented. Autotransplantation of BM-MSCs into the testicular network was achieved using microsurgicaltesticular sperm extraction (microTESE). Semen analysis and hormonal assessments were performed both before andsix months after treatment. Additionally, we conducted an in-silico analysis to explore potential protein-protein interactionsbetween exosomes secreted from BM-MSCs and receptors present in human seminiferous tubule cells. Results: Our results revealed significant improvements following treatment, including increased testosterone and inhibin Blevels, elevated sperm concentration, and reduced levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), andprolactin. Notably, in nine patients (22.5%) previously diagnosed with secondary infertility and exhibiting azoospermia beforetreatment, the proposed approach yielded successful outcomes, as indicated by hormonal profile changes over six months.Importantly, these improvements were achieved without complications. Additionally, our in-silico analysis identified potentialbinding interactions between the protein content of BM-MSC-derived exosomes and receptors integral to spermatogenesis. Conclusion: Autotransplantation of BM-MSCs into the testicular network using microTESE in NOA patients led to the regenerationof seminiferous tubules and the regulation of hormonal profiles governing spermatogenesis. Our findings supportthe safety and effectiveness of autologous BM-MSCs as a promising treatment modality for NOA, with a particular focus onthe achieved outcomes in patients with secondary infertility (registration number: IRCT20190519043634N1).