Melatonin-Pretreated Mesenchymal Stem Cell-Derived Exosomes Alleviate Cavernous Fibrosis in a Rat Model of Nerve Injury-induced Erectile Dysfunction via miR-145-5p/TGF-β/Smad Axis

Backgrounds: Cavernous nerve injury-induced erectile dysfunction (CNI-ED) is a common complication after radical prostatectomy. As a consequence of the concomitant severe fibrosis of the corpus cavernosum, conventional treatment approaches have had little success. Methods: Pre-treatment of adipose-derived stem cells with melatonin allows for the extraction of active exosomes (MT-hASC-EVs) from the conditioned medium. The therapeutic effects of MT-hASC-EVs were assessed in a rat model of CNI-ED, and the anti-fibrotic properties were evaluated. MicroRNA sequencing was used to identify specific microRNAs highly expressed in MT-hASC-EVs, and differential microRNAs were screened for regulatory pathways through target gene enrichment analysis. Finally, the conclusions from bioinformatics analysis were validated through in vitro experiments. Results: Intracavernous injection of MT-hASC-EVs significantly restored erectile function and reduced the extent of corpus cavernosum fibrosis in the CNI-ED rat model. MT-hASC-EVs promoted the proliferation and anti-apoptotic effects of CCSMCs in vitro. Mechanistically, MT-hASC-EVs inhibit fibrosis by delivering miR-145-5p, which targets TGF-β2/Smad3 axis. Conclusions: MT-hASCs-EVs can inhibit cavernous fibrosis and improve erectile function in a rat model of CNI-ED by targeting the miR-145-5p/TGF-β/Smad axis.