Extracellular vesicles propagate aging in COPD airway epithelial cells by transfer of microRNA-34a

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is associated with the acceleration of lung aging, demonstrated by the accumulation of senescent cells in lung tissue. MicroRNA (miR)-34a is induces senescence by suppressing the key anti-aging molecule, sirtuin-1 (SIRT1). Senescent cells spread senescence to neighboring and distant cells, which favors the progression of COPD and its comorbidities. The mechanisms for spreading senescence remain undetermined but may be mediated by the transfer of microRNAs in extracellular vesicles. Objectives To analyze the miRNA content of extracellular vesicles in COPD and explore their effect on cellular senescence of healthy cells Methods 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. Main Results EVs from COPD cells induce senescence in healthy recipient cells via the selective transfer of miR-34a. We showed that 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, such as p21 CIP1 and positive staining for senescence-associated β-galactosidase Conclusions 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.