Adipose-derived mesenchymal stem cell secretome promotes testicular regeneration following chemically induced injury: A review of preclinical studies

Abstract

Introduction: Male infertility is a rising problem globally with male factors contributing up to 50% of all couple infertility cases. The sperm quality decline raises serious concerns regarding future population sustainability and male reproductive health. Adipose-derived mesenchymal stem cell (AdMSC) secretome, defined as a cell-free product comprising paracrine factors secreted by these cells, has emerged as a promising cell-free regenerative therapy for testicular injury, offering advantages of accessibility and therapeutic potential. This systematic review aimed to evaluate the effectiveness of AdMSC secretome in chemically induced testicular injury models. Methods: A systematic literature search was conducted across four electronic databases (PubMed, Google Scholar, OVID and Cochrane) covering publications from 2015 to 2025. Preclinical studies investigating the therapeutic effects of AdMSC secretome in murine models of chemically induced testicular injury were included. Results: Three preclinical studies utilizing male murine models were analysed. Testicular injury was induced using busulfan, doxorubicin or acrylamide. AdMSC secretome was administered via intra-testicular injection (n = 2) and intravenous injection (n = 1). All studies demonstrated partial regeneration of seminiferous tubule in secretome-treated groups compared with controls. Two studies reported reduced cellular apoptosis using TUNEL assay and acridine orange staining. An increase in Leydig cell numbers was observed following secretome treatment, while Sertoli cells remained unchanged. One study identified vascular endothelial growth factor (VEGF) as a key paracrine mediator, with anti-VEGF intervention abolishing the therapeutic effect. Testosterone levels were consistently higher in secretome-treated groups compared to those receiving AdMSC transplantation. Conclusions: AdMSC secretome demonstrates therapeutic potential in chemically-induced testicular injury by promoting seminiferous tubule regeneration, reducing apoptosis, and enhancing Leydig cell recovery, with VEGF playing a critical mechanistic role. These findings support the potential AdMSC secretome as a cell-free regenerative approach for male infertility.