hUC-MSC-derived extracellular vesicles protect lung tissue from cigarette smoke-induced injury by upregulating the METTL3-mediated m⁶A modification.

IF 4.7 2区生物学 Q2 CELL BIOLOGY

American journal of physiology. Cell physiology Pub Date : 2025-08-01 Epub Date: 2025-06-23 DOI:10.1152/ajpcell.00222.2025

Jun Wen, Jianwei Xu, Ying Li, Lijuan Ma, Jie Wang, Shan Huang, Xue Yi

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引用次数: 0

Abstract

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), a prevalent and incurable lung disease. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) exhibit therapeutic potential in treating COPD. However, the precise mechanism underlying their beneficial effects in lung epithelial cells exposed to cigarette smoke remains incompletely understood. In this study, we purified hUC-MSC-EVs and assessed their influence on viability, apoptosis, and pyroptosis in BEAS-2B human bronchial epithelial cells treated with cigarette smoke extract (CSE). Our data revealed that CSE-treated BEAS-2B cells uptake hUC-MSC-EVs, which significantly improved cell viability and suppressed apoptosis and pyroptosis. Mechanistically, hUC-MSC-EVs partially restored the decreased N⁶-methyladenosine (m⁶A) modification, a key regulator of COPD, in CSE-treated BEAS-2B cells by upregulating the m⁶A writer METTL3. Depletion of METTL3 abolished the protective effect of hUC-MSC-EVs against CSE-induced damage in BEAS-2B cells. The levels of METTL3 were also positively associated with the Wnt/β-catenin pathway. In addition, we investigated the protective effect of hUC-MSC-EVs on lung tissues in a COPD rat model, confirming the regulation of METTL3 expression and the Wnt/β-catenin pathway by hUC-MSC-EVs in vivo. These findings collectively validate the protective effect of hUC-MSC-EVs on lung epithelial cells exposed to cigarette smoke and highlight the therapeutic potential of targeting the METTL3-Wnt axis in COPD treatment.NEW & NOTEWORTHY hUC-MSC-EVs partially restored the decreased m⁶A modification in cigarette smoke extract (CSE)-treated BEAS-2B cells by upregulating METTL3. Depletion of METTL3 abolished the protective effect of hUC-MSC-EVs against CSE-induced damage in BEAS-2B cells. hUC-MSC-EVs regulate the expression of METTL3 and Wnt/β-catenin pathway in vivo. Therefore, hUC-MSC-EVs have a protective effect on lung epithelial cells exposed to cigarette smoke, and targeting the METTL3-Wnt axis has therapeutic potential in chronic obstructive pulmonary disease.

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huc - msc衍生的细胞外囊泡通过上调mettl3介导的m6A修饰来保护肺组织免受香烟烟雾引起的损伤。

吸烟是导致慢性阻塞性肺疾病（COPD）的主要原因，慢性阻塞性肺疾病是一种普遍且无法治愈的肺病。人脐带间充质干细胞来源的细胞外囊泡（hUC-MSC-EVs）在治疗COPD方面显示出治疗潜力。然而，它们对暴露于香烟烟雾中的肺上皮细胞有益作用的确切机制仍不完全清楚。在这项研究中，我们纯化了huc - msc - ev，并评估了它们对香烟烟雾提取物（CSE）处理的BEAS-2B人支气管上皮细胞的活力、凋亡和焦亡的影响。我们的数据显示，cse处理的BEAS-2B细胞摄取huc - msc - ev，显著提高了细胞活力，抑制了细胞凋亡和焦亡。在机制上，huc - msc - ev通过上调m6A转录因子METTL3，部分恢复了cse处理的BEAS-2B细胞中减少的m6A修饰，m6A修饰是COPD的关键调节因子。METTL3的缺失消除了huc - msc - ev对cse诱导的BEAS-2B细胞损伤的保护作用。METTL3水平也与Wnt/β-catenin通路呈正相关。此外，我们在COPD大鼠模型中研究了huc - msc - ev对肺组织的保护作用，证实了huc - msc - ev在体内调节METTL3表达和Wnt/β-catenin通路。这些发现共同验证了huc - msc - ev对暴露于香烟烟雾的肺上皮细胞的保护作用，并强调了靶向METTL3-Wnt轴在COPD治疗中的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

American journal of physiology. Cell physiology 生物-生理学

CiteScore

9.10

自引率

1.80%

发文量

252

审稿时长

1 months

期刊介绍： The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.