MiR-148a-3p Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviates Silica-Induced Pulmonary Fibrosis by Inhibiting β-Catenin Signaling.

Background: In clinical practice, due to the lack of typical symptoms and specific diagnostic biomarkers, silicotic patients often having already developed pulmonary fibrosis by the time of clinical diagnosis. Studies have demonstrated that human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs) could moderate silicosis fibrosis, which may be related to the microRNAs (miRNAs) in hucMSC-EVs. While the full extent of their antifibrotic effects and the underlying mechanisms remain to be elucidated. Methods: HucMSC-EVs were administered from day 28 to day 56 after silica exposure in mice, which in a therapeutic manner. In addition, the antifibrotic abilities of engineered hucMSC-EVs with varying levels of miR-148a-3p, a miRNA with antifibrotic properties, were evaluated. Heat shock protein 90 beta family member 1 (Hsp90b1) is reported to be a target of miR-148a-3p, the protein-protein interaction analysis was used to explore its regulated downstream factors in lung fibrosis. The underlying mechanisms were also investigated by using miR-148a-3p mimics and small interfering RNA (siRNA) targeting Hsp90b1 in vitro. Results: HucMSC-EVs could reduce the histopathological changes and the levels of fibrotic proteins in the mouse lung tissues when administered in a therapeutic manner. Meanwhile, miR-148a-3p-overexpressed hucMSC-EVs intervention exhibited the enhanced anti-fibrotic effect compared with the negative control intervention group. In vitro, the elevated level of miR-148a-3p in hucMSC-EVs was shown to enhance hucMSC-EVs' inhibition of fibroblast collagen hypersecretion, whereas a depressed level of miR-148a-3p in hucMSC-EVs partially counteracted the inhibitory effect. Moreover, the mechanistic investigations revealed that miR-148a-3p could blunt β-catenin signaling via targeting Hsp90b1 in fibroblasts. Conclusion: This study demonstrated that hucMSC-EVs retain their antifibrotic properties in silicotic mice when administered in a therapeutic manner. Further, miR-148a-3p was confirmed to be an essential component within hucMSC-EVs, mediating their inhibition of silica-induced pulmonary fibrosis by reducing β-catenin signaling via targeting of Hsp90b1 in fibroblasts.