Exosomal miR-17-5p derived from epithelial cells is involved in aberrant epithelium-fibroblast crosstalk and induces the development of oral submucosal fibrosis.

Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development. The epithelium, which is the first line of defense against the external environment, can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment. However, the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear. In this study, we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes. MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts, where it promoted cell secretion, contraction, migration and fibrogenic marker (α-SMA and collagen type I) expression. The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-ß receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-ß pathway signaling. Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes. Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts. In conclusion, we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-ß fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.

The novel insights of epithelial-derived exosomes in various fibrotic diseases.

The characteristics of fibrosis include the abnormal accumulation of extracellular matrix proteins and abnormal tissue repair caused by injury, infection, and inflammation, leading to a significant increase in organ failure and mortality. Effective and precise treatments are urgently needed to halt and reverse the progression of fibrotic diseases. Exosomes are tiny vesicles derived from endosomes, spanning from 40 to 160 nanometers in diameter, which are expelled into the extracellular matrix environment by various cell types. They play a crucial role in facilitating cell-to-cell communication by transporting a variety of cargoes, including proteins, RNA, and DNA. Epithelial cells serve as the primary barrier against diverse external stimuli that precipitate fibrotic diseases. Numerous research suggests that exosomes from epithelial cells have a significant impact on several fibrotic diseases. An in-depth comprehension of the cellular and molecular mechanisms of epithelial cell-derived exosomes in fibrosis holds promise for advancing the exploration of novel diagnostic biomarkers and clinical drug targets. In this review, we expand upon the pathogenic mechanisms of epithelium-derived exosomes and highlight their role in the fibrotic process by inducing inflammation and activating fibroblasts. In addition, we are particularly interested in the bioactive molecules carried by epithelial-derived exosomes and their potential value in the diagnosis and treatment of fibrosis and delineate the clinical utility of exosomes as an emerging therapeutic modality, highlighting their potential application in addressing various medical conditions.

Mechanisms and markers of malignant transformation of oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic premalignant disease associated with betel quid chewing. Epidemiological studies indicate that there are approximately 5 million individuals suffering from OSF worldwide, with a concerning malignancy transformation rate of up to 4.2 %. When OSF progresses to oral squamous cell carcinoma (OSCC), the 5-year survival rate for OSCC drops to below 60 %. Therefore, early screening and diagnosis are essential for both preventing and effectively treating OSF and its potential malignant transformation. Numerous studies have shown that the malignant transformation of OSF is associated with various factors, including epigenetic reprogramming, epithelial-mesenchymal transition, hypoxia, cell cycle changes, immune regulation disturbances, and oxidative damage. This review article focuses on the unraveling the potential mechanisms underlying the malignant transformation of OSF, as well as the abnormal expression of biomarkers throughout this transformative process, with the aim of aiding early screening for carcinogenic changes in OSF. Furthermore, we discuss the significance of utilizing blood and saliva components from patients with OSF, along with optical diagnostic techniques, in the early screening of OSF malignant transformation.