COPD Airway Epithelial Cell-derived Extracellular Vesicles Spread Cellular Senescence via MicroRNA-34a.

Abstract

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^CIP1 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^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 of the elderly.