Human mesenchymal stem cell exosomes attenuate inflammation of lung epithelial cells through miR-223 in acute lung injury

Abstract

Acute lung injury (ALI), characterized by alveolar epithelial damage and uncontrolled pulmonary inflammation, is a life-threatening disease with high morbidity and mortality. Exosomes, secreted by multiple types of cells, are critical cellular communication mediators and can inhibit inflammation by transferring bioactive molecules such as microRNA (miRNA). Thus, we hypothesized that exosomes derived from mesenchymal stem cells (MSC) could transfer of miRNA to attenuate inflammation of lung epithelial cells during ALI. MSC-exosomes were collected by ultracentrifugation and subcutaneously injected into lipopolysaccharide (LPS)-induced ALI mouse model via the tail vein. After 48 hours, mice were sacrificed for evaluation of pulmonary microvascular permeability and inflammatory responses. In vitro, A549 cells and primary human small airway epithelial cells (SAEC) were subjected to LPS with or without the treatment of MSC-exosomes. MSC exosomes treatment not only improved pulmonary microvascular permeability, but also mediated a down-regulation of proinflammatory responses (reducing Cxcl1, IL-1β, IL-6 and TNF-α) and an up-regulation of anti-inflammatory responses (increasing cytokine IL-10). In vitro, MSC exosomes could inhibit inflammation induced by LPS in A549 cells and SAEC cells. Notably, miR-223 was found to be highly enriched in exosomes and served as a critical mediator in MSC exosomes induced regulatory effects through inhibition of poly (adenosine diphosphate-ribose) polymerase–1 (PARP-1) in lung epithelial cells. Together, these findings suggest that MSC exosomes can be used as a novel promising strategy for ALI.