# Adipose‐derived stem cell exosomes alleviate TGF‐β1‐induced urethral stricture fibrosis by suppressing the TGF‐β/Smad pathway and downstream PDGFR‐β/RAS/ERK signaling

## TL;DR

Exosomes from fat cells reduce urethral scarring by blocking key signaling pathways, offering a new non-invasive treatment for fibrotic diseases.

## Contribution

The study identifies a dual pathway mechanism by which ADSC exosomes alleviate fibrosis, providing a novel cell-free therapeutic strategy.

## Key findings

- ADSC exosomes improved urodynamic function and reduced collagen in fibrotic tissue.
- Exosome treatment suppressed TGF-β/Smad and PDGFR-β/RAS/ERK pathways in fibroblasts.
- In vivo and in vitro results confirmed the hierarchical regulation of fibrosis signaling.

## Abstract

This study aimed to investigate the therapeutic effects and underlying mechanisms of adipose‐derived stem cell exosomes (ADSCs‐exo) in ameliorating fibrosis in a rat model. ADSCs were isolated and cultured from rat adipose tissue, and ADSCs‐exo were extracted via ultracentrifugation. Urethral fibrosis was induced by local injection of TGF‐β1 (10 μg), followed by ADSCs‐exo treatment. Urodynamic parameters were evaluated, and histological changes were evaluated using hematoxylin and eosin and Masson staining. Transcriptomic analysis and pathway enrichment were performed to identify signaling pathways regulated by ADSCs‐exo. In vitro, urinary fibroblasts were stimulated with TGF‐β1 and treated with ADSCs‐exo alone or in combination with PDGF‐BB (agonist) or imatinib (inhibitor). ADSCs‐exo treatment significantly improved urodynamic function, reduced collagen deposition, and suppressed fibrosis‐related protein expression in vivo. Transcriptomic analysis revealed platelet‐derived growth factor and TGF‐β pathways as major contributors to fibrosis. In vitro, ADSCs‐exo significantly reduced TGF‐β1‐induced fibroblast proliferation, migration, and fibrosis‐related protein expression, effects that were reversed by PDGF‐BB and enhanced by imatinib. These findings were consistent in vivo, further supporting the hierarchical regulation of fibrosis‐related signaling by ADSCs‐exo. ADSCs‐exo mitigates urethral stricture fibrosis by primarily suppressing the TGF‐β/Smad pathway, thereby downregulating the downstream PDGFR‐β/RAS/ERK axis, highlighting its therapeutic potential as a cell‐free therapeutic approach for fibrotic urethral disease.

Adipose‐derived stem cell exosomes alleviate TGF‐β1‐induced urethral fibrosis by inhibiting the PDGFR‐β/RAS/ERK signaling axis. This study reveals a dual regulatory mechanism through both the TGF‐β/Smad and platelet‐derived growth factor pathways, offering a promising noninvasive strategy for fibrotic disease treatment and urethral stricture prevention.