Cell-based Therapies for Azoospermia: Current Status and Future Directions

Rano Amirkhanovna Zhankina

2025

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DOI 10.4103/wkrj.wkrj_3_26
Data confidence 70 medium
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Abstract

Background: Nonobstructive azoospermia (NOA) remains one of the most difficult causes of male infertility because spermatogenesis is severely impaired, and pharmacologic treatments rarely restore sperm production. Surgical sperm retrieval (e.g., microdissection testicular sperm extraction) enables assisted reproduction in some patients, but many men have no retrievable sperm. Objective: The study aimed to summarize current evidence on cell-based therapies for azoospermia, integrating data from animal studies and early clinical trials, and to highlight mechanisms, limitations, and future directions. Methods: Evidence from experimental models and human studies was synthesized, focusing on mesenchymal stromal/stem cells (MSCs), spermatogonial stem cell (SSC) transplantation, Sertoli cell-based niche restoration, and testicular tissue grafting. Outcomes of interest included histologic recovery of spermatogenesis, sperm detection/retrieval, endocrine changes, fertility endpoints, and safety. Results: In animal models of chemotherapy- or toxin-induced testicular failure, intratesticular MSCs (bone marrow or adipose-derived) frequently improved seminiferous architecture, increased germ-cell markers, and restored sperm production, with occasional fertility recovery. Proposed mechanisms are predominantly paracrine and include antiapoptotic, anti-inflammatory, antioxidant, and proangiogenic effects, plus modulation of Leydig/Sertoli cell function and microRNA signaling. SSC transplantation has achieved donor-derived spermatogenesis in multiple species and functional sperm production in primates, while autografting cryopreserved prepubertal testicular tissue has produced sperm and live offspring in nonhuman primates. Early human studies of autologous MSC delivery in NOA suggest feasibility and potential endocrine and spermatogenic benefits in a subset of patients, with short-term safety signals favorable. Conclusions: Cell-based therapies for azoospermia are advancing from proof of concept to early clinical translation, but require standardized protocols, controlled trials with reproductive endpoints, and long-term safety monitoring.