Adipose-Derived Stem Cell-Derived Extracellular Vesicles Inhibit the Fibrosis of Fibrotic Buccal Mucosal Fibroblasts via the MicroRNA-375/FOXF1 Axis

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.

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis

“…As described above, PI3K is an upstream regulator of LOXL2, suggesting that this miR-375 may be involved in LOXL2-induced myocardial fibrosis. However, it has previously been shown that the activation of the miR-375/FOXF1 axis in exosomes inhibits fibrosis (46). Thus, a number of miRNAs are associated with diabetic heart failure and cuproptosis, and miR-375 likely interacts with LOXL2 and participates in the development of myocardial fibrosis, while also having an anti-fibrotic effect in combination with miR-27b-3p in exosomes.…”

Accumulated X-ray irradiation induces miR-187-5p upregulation mediating fibrotic buccal mucosal fibroblasts activities via DKK2

“…miR-10b, miR-1246, and miR-375 have been indicated to regulate the activation of myofibroblasts and therefore mediate the progression of oral submucous fibrosis. 11 , 12 , 13 The involvement and regulatory effect of miR-187-5p in the activation of myofibroblast were evaluated in the present study, which could benefit the evaluation of X-ray dangers on oral mucous cells.…”

Obesity-Associated ECM Remodeling in Cancer Progression

“…Adipocytes, myofibroblasts, and fibroblasts are the major cellular components in the adipose tissue responsible for ECM production. Excessive collagen deposition and enhanced collagen alignment in adipose tissue have been observed in various models of obesity [ 9 , 10 , 11 , 12 , 13 ]. The connection between the fibrotic pathology and obesity-related metabolic disorders has been established [ 14 , 15 ].…”