Targeting miR-133-3p via mesenchymal stem cells-derived exosomes as a novel cell-free therapy for testosterone-induced benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH), the leading cause of lower urinary tract symptoms (LUTS), is commonly treated with conventional therapies that often have undesirable side effects. Safer alternatives such as bone marrow mesenchymal stem cells (BM-MSCs)-derived exosomes (MSCs-Exo) could represent a novel strategy for attenuation of disease progression. The objective of this study was to evaluate MSCs-Exo as a cell-free therapy for BPH and explore its protective effect. Eighteen acclimatized male adult rats were allocated randomly into three groups: normal control group, BPH group, and BPH group treated with MSCs-Exo. BPH was established by s.c. injection of testosterone enanthate (3 mg/ Kg) five days per week over a two-week period. The MSCs-Exo were isolated and identified by transmission electron microscopy and flowcytometric detection of the exosome-specific surface markers: CD9 and CD63. MSCs-Exo were administered by i.p. injection (100 µg protein) once per week for two weeks. MSCs-Exo significantly decreased the prostate index and prostate-specific antigen-like protein (PSA-like protein) compared to the BPH group. Immunohistochemical staining showed decreased expression of NF-κB p65, TNF-α, and β-catenin but increased expression of SIRT1 in MSCs-Exo group. Gene expression of β-catenin-related proteins, LRP6 and c-Myc, was measured by RT-qPCR and exhibited decreased expression in MSCs-Exo group. These observations were linked with the downregulation of miR-133-3p. MSCs-Exo exerted a potential prophylactic effect in BPH; it attenuated prostatic enlargement and showed anti-inflammatory and anti-proliferative activities, which could be through modulation of two pathogenic mechanisms mediated by miR-133-3p and β-catenin.