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

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.

Keywords: METTL3; Wnt/β-catenin pathway; chronic obstructive pulmonary disease; hUC-MSC-derived extracellular vesicles; pyroptosis.