Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury.

Ruoqiong Huang,Huikang Tao,Jiangmei Wang,Yaoqin Hu,Guanguan Qiu,Jianguo Xu,Chaojin Qin,Menghua Ge,Qiang Shu,Guoping Zheng

doi:10.18632/aging.102314

Abstract

Old age is a known risk factor for mortality in acute respiratory distress syndrome (ARDS)/acute lung injury. Mesenchymal stem cells (MSCs) possess potent immunomodulatory properties, while aging MSCs have reduced capacity. Recent studies have demonstrated that MSC-derived extracellular vesicles (MSC-EVs) are able to mimic MSCs in alleviating acute lung injury. The goals of this study were to determine whether EVs from young and aging MSCs had differential effects on lipopolysaccharide (LPS)-induced lung injury in young mice and unravel the underlying mechanisms. Our results showed that both aging and young MSC-EVs had similar physical and phenotypical properties. As their parental cells, young MSC-EVs alleviated LPS-induced acute lung injury, while aging MSC-EVs did not exhibit the protective effects. In contrast to young MSC-EVs, aging MSC-EVs failed to alter macrophage phenotypes and reduce macrophage recruitment. In addition, the internalization of aging MSC-EVs by macrophages was significantly lower compared with that of young MSC-EVs. Furthermore, aging and young MSC-EVs differed in levels of several miRNAs relating macrophage polarization. In conclusion, aging and young MSC-EVs have differential effects in alleviating acute lung injury and macrophage polarization, which may be associated with internalization of EVs and their miRNA content.

Highlights

Acute respiratory distress syndrome (ARDS)/acute lung injury, which is characterized by acute hypoxemia and bilateral opacities on chest radiograph, is one of the common complications of critical illnesses and a lifethreatening lung disease [1]
In a mouse model of acute lung injury induced by endotoxemia, Bustos et al showed that aging Mesenchymal stem cells (MSCs) lacked the anti-inflammatory effects [21]
The present study demonstrates that aging MSC-derived extracellular vesicles (MSC-EVs) have impaired therapeutic effects in a murine model of LPS-induced acute lung injury compared with young MSC-EVs

Summary

Introduction

Acute respiratory distress syndrome (ARDS)/acute lung injury, which is characterized by acute hypoxemia and bilateral opacities on chest radiograph, is one of the common complications of critical illnesses and a lifethreatening lung disease [1]. Hospital mortality of ARDS is still at a high rate of 30%~40%, even though treatments for ARDS have improved recently, including extracorporeal carbon dioxide removal, high-frequency oscillatory ventilation, lung recruitment maneuver, and prone positioning [2]. Resident macrophages are activated and skewed toward an M1 activation state with the secretion of proinflammatory cytokines. Neutrophils are recruited to promote the inflammatory responses. The severe inflammatory responses lead to lung endothelial injury, alveolar epithelial injury, and the accumulation of protein-rich fluid in the alveolar space [3]. Treatment with mesenchymal stem cells (MSCs) might be such an ideal approach. MSCs exert their immunomodulatory effects via inhibiting proliferation and activity of natural killer cells, suppressing proliferation and activation of T and B lymphocytes, and blocking maturation of dendritic cells

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