Work

Airway basal stem cell-derived extracellular vesicles drive ECM remodeling and suppress fibroblasts activation via the miR-30a-5p/FAP axis in benign tracheal stenosis

Year: 2025

Type: article

Abstract: • First study to propose airway BSC-EVs as a therapeutic intervention for benign tracheal stenosis (BTS). • Multi-dimensional analyses dynamically track BTS progression and BSC-EV treatment response. • BSC-EVs restore ECM homeostasis and prevent fibrosis, offering a novel strategy for BTS treatment. • BSC-EVs uniquely drive adaptive ECM remodeling and collagen alignment in BTS models. • miR-30a-5p in BSC-EVs directly targets FAP to inhibit fibroblast activation and ECM deposition. Benign tracheal stenosis (BTS) is characterized by granulation tissue hyperplasia, driven by abnormal fibroblast activation and excessive extracellular matrix deposition. Targeting these mechanisms with novel therapies may offer a promising approach to addressing or preventing re-stenosis. Our previous study demonstrated that airway basal stem cell (BSC) transplantation can inhibit granulation hyperplasia in BTS. Given the therapeutic potential of extracellular vesicles (EVs) as mediators in cell-based therapies, we investigated the in vivo efficacy of airway BSC-derived EVs (BSC-EVs) and explored their underlying mechanisms. BTS was induced in rabbits via tracheal mucosal injury. BSC-EVs were isolated, characterized, and intratracheally delivered. Then, therapeutic effects were evaluated using bronchoscopy, 18 F-FAPI PET/CT, histology, and RNA-seq. The underlying mechanisms were investigated in vitro focusing on miRNA regulation of human airway fibroblasts (AFs). Our findings revealed that BSC-EVs significantly reduce granulation hyperplasia, promote ECM remodeling and improve collagen fiber alignment, leading to enhanced airway patency and prolonged survival. Mechanistically, we identified miR-30a-5p as a key functional cargo within BSC-EVs, which directly targets the fibroblast activation protein (FAP) gene. In vitro experiments demonstrated that miR-30a-5p mediates the anti-fibrotic effects of BSC-EVs by attenuating fibroblast activation, collagen contraction, and ECM deposition. These findings suggest that BSC-EVs represent a promising therapeutic strategy for BTS by inhibiting fibroblast activation and promoting ECM remodeling via the miR-30a-5p/FAP axis, offering a novel advancement beyond current treatment approaches.

Source: Journal of Advanced Research

DOI: 10.1016/j.jare.2025.08.014