Devulder Justine V, Baker Jonathan R, Fenwick Peter S, Odqvist Lina, Donnelly Louise E, Barnes Peter J
Imperial College London National Heart and Lung Institute, London, United Kingdom of Great Britain and Northern Ireland;
Imperial College London, Airway Disease Section, London, United Kingdom of Great Britain and Northern Ireland.
Am J Respir Cell Mol Biol. 2025 Jan 21. doi: 10.1165/rcmb.2024-0183OC.
Chronic obstructive pulmonary disease (COPD) is associated with the acceleration of lung aging, and the accumulation of senescent cells in lung tissue. MicroRNA (miR)-34a induces senescence by suppressing the anti-aging molecule, sirtuin-1 (SIRT1). Senescent cells spread senescence to neighbouring and distant cells, favouring COPD progression and its comorbidities. Mechanisms for spreading senescence remain undetermined but may be mediated by the transfer of microRNAs in extracellular vesicles. We analysed the miRNA content of extracellular vesicles in COPD and explored their effect on cellular senescence of healthy cells. EVs were isolated from small airway epithelial cells (SAEC) from healthy donors or COPD patients. Recipient healthy SAEC were cultured with EVs and the expression of miR-34a and markers of cellular senescence, p21 and SIRT1, were measured. We have shown that EVs from COPD cells induce senescence in healthy recipient cells via the selective transfer of miR-34a. COPD SAEC produce increased numbers of EVs enriched with miR-34a. EVs are taken up by healthy cells, resulting in reduced expression of the anti-aging molecule sirtuin-1 and increased expression of markers of senescence, like p21 and positive staining for senescence-associated β-galactosidase, which were blocked by a specific miR-34a antagomir. Our findings provide evidence of the mechanism by which EVs spread cellular senescence in human primary cells via miR-34a, rather than via soluble mediators. EVs enriched with miR-34a may spread senescence locally, accounting for disease progression, but also provide a mechanism for distant spread to account for comorbidities and multimorbidity of the elderly.
慢性阻塞性肺疾病（COPD）与肺衰老加速以及肺组织中衰老细胞的积累有关。微小RNA（miR）-34a通过抑制抗衰老分子沉默调节蛋白-1（SIRT1）诱导细胞衰老。衰老细胞将衰老传播至邻近和远处的细胞，促进COPD进展及其合并症的发生。衰老传播的机制尚不清楚，但可能由细胞外囊泡中微小RNA的转移介导。我们分析了COPD患者细胞外囊泡中的微小RNA含量，并探讨了它们对健康细胞衰老的影响。从健康供体或COPD患者的小气道上皮细胞（SAEC）中分离出细胞外囊泡（EVs）。将健康的受体SAEC与EVs共同培养，并检测miR-34a以及细胞衰老标志物p21和SIRT1的表达。我们发现，COPD细胞来源的EVs通过miR-34a的选择性转移诱导健康受体细胞衰老。COPD患者的SAEC产生更多富含miR-34a的EVs。健康细胞摄取EVs后，导致抗衰老分子沉默调节蛋白-1的表达降低，衰老标志物如p21的表达增加以及衰老相关β-半乳糖苷酶染色阳性，而这些变化可被特异性的miR-34a拮抗剂阻断。我们的研究结果提供了证据，证明EVs通过miR-34a而非可溶性介质在人类原代细胞中传播细胞衰老。富含miR-34a的EVs可能在局部传播衰老，这与疾病进展有关，但也为远处传播提供了一种机制，可解释老年人的合并症和多种疾病。
