HUMAN CELLS AND THEIR SECRETOME AS A TOOL FOR REGENERATIVE PHARMACOLOGY
Abstract
This report presents the results of studies on the fundamental mechanisms of stem cell niche restoration under the influence of MSCs and their secretome. The spermatogonial stem cell (SSC) niche was used as a model in two experimental injury settings – abdominal cryptorchidism in rats and doxorubicin-induced toxicity in mice. After injury, an increase in the number of tissue-specific MSCs in the testicular interstitium was observed, indicating their recruitment to the damage site. Local administration of both MSCs themselves and their secretome under the tunica albuginea led to restoration of both the structure and function of the SSC niche: the number of atrophic and fibrotic seminiferous tubules decreased, the blood-testis barrier was restored, total sperm count and motility increased, and partial recovery of fertility was noted at later time points. The cellular mechanisms included stimulation of spermatogenic cell proliferation, enhanced migration of Sertoli cells, and normalisation of Leydig cell secretory activity with a return of testosterone levels to physiological values. Using inhibitory analysis, vascular endothelial growth factor (VEGF) and microRNA-21 were identified as key secretome components mediating the regenerative effects of MSCs: their blockade significantly reduced the stimulatory effect on testosterone production by Leydig cells. In addition, the MSC secretome exerted pronounced anti-fibrotic effects, suppressing fibroblast-to-myofibroblast differentiation and reducing collagen deposition, which was mediated, in part, by microRNA-29c and -129 transported within extracellular vesicles.
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