Chronic Obstructive Pulmonary Disease Airway Epithelial Cell-derived Extracellular Vesicles Spread Cellular Senescence via MicroRNA-34a.

Chronic obstructive pulmonary disease (COPD) is associated with the acceleration of lung aging and the accumulation of senescent cells in lung tissue. MicroRNA-34a (miR-34a) induces senescence by suppressing the antiaging molecule sirtuin-1 (SIRT1). Senescent cells spread senescence to neighboring and distant cells, favoring COPD progression and its comorbidities. Mechanisms for spreading senescence remain undetermined but may be mediated by the transfer of microRNAs in extracellular vesicles (EVs). We analyzed the microRNA content of EVs in COPD and explored their effect on cellular senescence of healthy cells. EVs were isolated from small airway epithelial cells (SAECs) from healthy donors or patients with COPD. Recipient healthy SAECs were cultured with EVs, and the expression of miR-34a and markers of cellular senescence p21^CIP1 (cyclin-dependent kinase inhibitor-1) and SIRT1 was measured. We have shown that EVs from COPD cells induce senescence in healthy recipient cells via the selective transfer of miR-34a. COPD SAECs produce increased numbers of EVs enriched with miR-34a. EVs are taken up by healthy cells, resulting in reduced expression of the antiaging molecule SIRT1 and increased expression of markers of senescence, such as p21^CIP1 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 in elderly individuals.