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

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
Changqing Xie, Liang Zhong, Hui Feng, Rifu Wang, Yuxin Shi, Yonglin Lv, Yanjia Hu, Jing Li, Desheng Xiao, Shuang Liu, Qianming Chen, Yongguang Tao
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Abstract

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-β receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-β 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-β fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.

Abstract Image

源自上皮细胞的外泌体 miR-17-5p 参与了上皮细胞与成纤维细胞的异常串扰,并诱发了口腔黏膜下纤维化的发展。
口腔黏膜下纤维化(OSF)是一种由咀嚼槟榔引起的慢性炎症性黏膜疾病,属于口腔潜在恶性疾病。成纤维细胞分化异常导致胶原代谢紊乱是口腔黏膜下纤维化发生的核心过程。上皮是抵御外界环境的第一道防线,可以将外界信号转化为病理信号,并参与纤维化微环境的重塑。然而,上皮细胞驱动成纤维细胞分化的具体机制仍不清楚。在这项研究中,我们发现暴露于甲状腺素的上皮细胞通过分泌外泌体与纤维化微环境进行交流。MiR-17-5p 被包裹在上皮细胞衍生的外泌体中,并被成纤维细胞吸收,促进了细胞分泌、收缩、迁移和纤维化标志物(α-SMA 和 I 型胶原)的表达。其潜在的分子机制涉及 miR-17-5p 靶向 Smad7 并通过 E3 泛素化连接酶 WWP1 抑制 TGF-β 受体 1(TGFBR1)的降解,从而促进下游 TGF-β 通路信号的传递。用miR-17-5p抑制剂处理成纤维细胞可逆转上皮源性外泌体诱导的收缩和迁移表型。外泌体 miR-17-5p 被证实是成纤维细胞表型转化的关键调节因子。总之,我们证明了阿雷科林会引发上皮细胞-成纤维细胞的异常串联,并发现上皮细胞衍生的miR-17-5p通过经典的TGF-β纤维化途径介导成纤维细胞分化,这为OSF的诊断和治疗提供了新的视角和策略。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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