Melatonin‐Primed Mesenchymal Stem Cells‐Derived Small Extracellular Vesicles Alleviated Neurogenic Erectile Dysfunction by Reversing Phenotypic Modulation

Abstract

Erectile dysfunction (ED) is an adverse side effect of pelvic surgery with no effective treatment. In this study, it is explored whether melatonin could improve the therapeutic effects of small extracellular vesicles (sEVs), derived from mesenchymal stem cells (MSCs), on cavernous nerve injury (CNI) ED, and the underlying mechanisms are investigated. The sEVs from melatonin‐pretreated MSCs (MT‐EVs) and MSCs (NC‐EVs) are isolated and applied to CNI ED. Transplantation of MT‐EVs remarkably increases erectile function and reduces phenotypic modulation in CNI ED rats. The therapeutic effects of MT‐EVs are superior to those of NC‐EVs. Sequencing implies that miR‐10a‐3p is enriched in MT‐EVs, and directly targets the protein kinase inhibitor α (PKIA). After the suppression of miR‐10a‐3p, the therapeutic actions of MT‐EVs are abolished, but are rescued by PKIA. Similarly, RhoA/ROCK is inhibited by MT‐EVs, but this action is reversed by suppressing miR‐10a‐3p, accompanied by corresponding changes in PKIA. In conclusion, transplantation of MT‐EVs could significantly alleviate CNI ED. MT‐EVs may relieve the phenotypic modulation of the corpora cavernosum smooth muscle cells via the miR‐10a‐3p/PKIA/RhoA/ROCK signaling axis. These nanovesicles should be potential therapeutic vectors or bioactive materials for CNI ED.

Recent advances in extracellular vesicle engineering and its applications to regenerative medicine

“…This analysis was based on previous reports on the transduction of the PKIA/RhoA/ROCK signal in endothelial cells [ 88 , 89 ]. As a result, it was evident that Mel-EV could effectively suppress the phenotypic regulation of CSMC through the miR-10a-3p/PKIA/RhoA/ROCK axis, leading to significant improvement in cavernous nerve injury erectile dysfunction (CNI ED) [ 90 ]. Analysis of selenium, a known factor that influences MSC proliferation, multipotency, and anti-inflammatory effects, treated ADMSC-derived EV (Sel-EV), produced results like those of EV characteristics regulated by the previously mentioned substances.…”

Mesenchymal stem cell‐derived extracellular vesicles: Recent therapeutics and targeted drug delivery advances

“…Some extensively used modification techniques include click chemistry‐based strategies for EV surface labelling using fluorescent beads, quantum dots, and supermagnetic particles, as shown in Figure 2. Studies indicate that MSC‐EVs have shown substantial therapeutic potential in various disease conditions without any modification (Chen et al., 2023, Rani et al., 2015, Yang et al., 2023, Zeng et al., 2022). However, these EVs are often complemented with specific formulations, adhesives, or hydrogels to increase their intrinsic therapeutic efficiencies (Liu et al., 2023, Wang et al., 2023).…”