Abstract
Oral submucous fibrosis (OSF) is a precancerous lesion. Adipose-derived stem cell- (ADSC-) derived extracellular vesicles (EVs) (ADSC-EVs) regulate multiple oral diseases. Hence, this study explored the mechanism of ADSC-EVs in OSF. ADSCs were transduced with microRNA- (miR-) 375 mimic. ADSC-EVs and miR-375-overexpressed ADSC-EVs (EVs-miR-375) were extracted and identified. miR-375 expression in EVs and fibrotic buccal mucosal fibroblasts (fBMFs) was detected. EV uptake by fBMFs was observed. The targeted relationship between miR-375 and forkhead box protein F1 (FOXF1) was predicted and verified. After EVs-miR-375 treatment or FOXF1 overexpression, fBMF cell proliferation, migration, invasion, and apoptosis were evaluated, and levels of apoptosis-related proteins (cleaved-caspase-3, Bax, and Bcl-2) and fibrosis markers (α-SMA, collagen I, and collagen III) were detected. Functional rescue experiments were further performed to verify the role of the miR-375/FOXF1 axis in OSF. miR-375 was notably upregulated in EVs-miR-375 and EVs-miR-375-treated fBMFs (all P < 0.001). ADSC-EVs carried miR-375 into fBMFs. fBMFs can internalize ADSC-EVs. EVs-miR-375 treatment markedly inhibited fBMF cell proliferation, migration, invasion, and fibrosis and promoted apoptosis (all P < 0.01). Moreover, miR-375 targeted FOXF1 in fBMFs. FOXF1 overexpression promoted fBMF cell biological behaviors and fibrosis, which were reversed after EVs-miR-375 treatment (P < 0.01 or P < 0.001). We highlighted that ADSC-EVs inhibited fBMF fibrosis and then suppressed OSF progression via the miR-375/FOXF1 axis.
Highlights
Oral submucous fibrosis (OSF) is a chronic and progressive disease, which affects the whole oral cavity, pharynx, and even the esophageal mucosa [1]
OSF may evolve to malignant tumors and greatly affects patient’s quality of life [27]
It has shown that Adipose-derived stem cell- (ADSC-)extracellular vesicles (EVs) help to reduce the fibrosis in mice [28]
Summary
Oral submucous fibrosis (OSF) is a chronic and progressive disease, which affects the whole oral cavity, pharynx, and even the esophageal mucosa [1]. 7%-30% of OSF evolves into malignant tumors, which seriously threaten global public health [2]. Fibroblasts are indispensable participants in OSF development, since their dysfunction and fibrosis can result in hypovascularity and subsequent oral mucosa blanching, tooth and gingival staining, and trismus [6]. A previous study has proposed that fibrotic buccal mucosal fibroblasts (fBMFs) are tightly implicated in OSF [7]. The underlying molecular mechanism of OSF initiation and progression remains elusive, and it is of a great value to identify novel biomarkers and targets for effective therapy of OSF
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