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Abstract
Exosomes derived from human mesenchymal stem cells (hMSCs) have the capacity to regulate various biological events associated with sepsis-induced acute respiratory distress syndrome (ARDS), including cellular immunometabolism, the production of proinflammatory cytokines, allowing them to exert therapeutic effects. However, little is known about which type of hMSC-derived exosomes (hMSC-exo) is more effective and suitable for the treatment of sepsis-induced ARDS. The purpose of this study is to compare the efficacy of hMSC-derived exosomes from human adipose tissue (hADMSC-exo), human bone marrow (hBMMSC-exo), and human umbilical cord (hUCMSC-exo) in the treatment of sepsis-induced ARDS. We cocultured lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells with the three kinds of hMSCs and found that all hMSCs reduced the glycolysis level and the content of lactic acid in macrophages. Accordingly, the expression of proinflammatory cytokines also decreased. Notably, the protective effects of hMSCs from adipose tissue were more obvious than those of bone marrow and umbilical cord hMSCs. However, this protective effect was eliminated when an exosome inhibitor, GW4869, was added. Subsequently, we extracted and cocultured hMSC-derived exosomes with LPS-stimulated RAW264.7 cells and found that all three kinds of exosomes exerted a similar protective effect as their parental cells, with exosomes from adipose hMSCs showing the strongest protective effect. Finally, an experimental sepsis model in mice was established, and we found that all three types of hMSCs have obvious lung-protective effects, in reducing lung injury scores, lactic acid, and proinflammatory cytokine levels in the lung tissues and decreasing the total protein content and inflammatory cell count in the bronchoalveolar lavage fluid (BALF), and also can attenuate the systemic inflammatory response and improve the survival rate of mice. Intravenous injection of three types of hMSC-exo, in particular those derived from adipose hADMSCs, also showed lung-protective effects in mice. These findings revealed that exosomes derived from different sources of hMSCs can effectively downregulate sepsis-induced glycolysis and inflammation in macrophages, ameliorate the lung pathological damage, and improve the survival rate of mice with sepsis. It is worth noting that the protective effect of hADMSC-exo is better than that of hBMMSC-exo and hUCMSC-exo.
Highlights
Sepsis is a common clinical syndrome that can lead to multiple life-threatening organ dysfunctions, including sepsisinduced acute lung injury (ALI), causing high mortality [1, 2]
HMSCs from adipose tissue exhibited the most significant inhibitory effect on the expression of M2 polarization markers in LPS-treated cells. These results suggest that coculture with human mesenchymal stem cells (hMSCs) reduces the production of inflammatory cytokines and inhibits the inflammatory response by downregulating the glycolysis levels in RAW264.7 cells, promoting their polarization toward M2 macrophages
We found that pretreatment with GW4869 for 24 h nearly eliminated the inhibitory effect of hMSCs on the expression of key enzymes in glycolysis (PKM2, hexokinase 2 (HK2), and lactic acid dehydrogenase A (LDHA)) in LPS-treated RAW264.7 cells (Figures 3(a)–3(d))
Summary
Sepsis is a common clinical syndrome that can lead to multiple life-threatening organ dysfunctions, including sepsisinduced acute lung injury (ALI), causing high mortality [1, 2]. The pathological process of ARDS is initiated by inflammatory cells, mainly neutrophils and macrophages, that accumulate and infiltrate into the alveolar tissues. This infiltration damages alveolar epithelial cells and capillary endothelial cells, increasing their permeability and leading to diffuse pulmonary interstitial and alveolar edema, which eventually result in refractory hypoxemia and progressive dyspnea [5]. Several studies from our own group and others have shown that specific metabolic characteristics of macrophages can modulate their polarization state and immune function [9, 10]. A transition in the polarization state of macrophages from M1 to M2 inhibits the inflammatory response and promotes tissue repair and regeneration [12, 13]
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