Mesenchymal Stem Cell-Derived Exosomes Induced by IL-1β Attenuate Urethral Stricture Through Let-7c/PAK1/NF-κB-Regulated Macrophage M2 Polarization

BACKGROUND: Urethral stricture is a clinical challenge for both patients and clinicians. Post-traumatic urethral stricture is associated with formation of scar tissue caused by excessive inflammation. The aim of this study is exploring potential therapeutic strategies for this condition. METHODS: In vivo experiments on New Zealand rabbits and in vitro experiments on THP-1 monocytes and urethral fibroblasts were performed to investigate the effects on post-traumatic urethral stricture of exosomes isolated from IL-1β-treated mesenchymal stem cells (Exo-MSCs(IL−1β)) and the role of macrophage M2 polarization in this process. Additionally, related signaling and mechanism behind were explored. RESULTS: In a New Zealand rabbit model of post-traumatic urethral stricture, injection of Exo-MSCs(IL−1β) significantly reduced urethral stricture and collagen fiber accumulation compared with Exo-MSCs. Addition of Exo-MSCs(IL−1β) to THP-1 monocytes in vitro induced M2 macrophage polarization, which, in turn, inhibited activation of urethral fibroblasts and synthesis of collagen. Mechanistically, Exo-MSCs(IL−1β) were found to contain high levels of the microRNA let-7c, and luciferase reporter assays showed that let-7c interacted with the 3′UTR of PAK1 mRNA. Transfection of THP-1 cells with a let-7c mimic downregulated PAK1 expression and inhibited activation of the NF-κB signaling pathway. CONCLUSION: These results support a role for let-7c-containing Exo-MSCs(IL−1β) in reducing urethral stricture via inhibition of PAK1–NF-κB signaling, M2 macrophage polarization, and differentiation of urethral myofibroblasts.