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Intratracheal and Systemic Administration of Mesenchymal Stem Cell-Derived Extracellular Vesicles Are Equally Effective in Ameliorating Acute Lung Injury
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A2960 - Intratracheal and Systemic Administration of Mesenchymal Stem Cell-Derived Extracellular Vesicles Are Equally Effective in Ameliorating Acute Lung Injury
Author Block: J. Wang1, R. Huang1, G. Zheng2, G. Qiu2, M. Ge2, Q. Xu3, Q. Shu1, J. Xu2; 1The Children’s Hospital of Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, China, 2Shaoxing Second Hospital, 123 Yanan Road, Shaoxing,Zhejiang, China, 3Zhejiang University School of Medicine,, Hangzhou, Zhejiang, Hangzhou, China.
Rationale: Several studies have demonstrated that administration of mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) either intratracheally or systemically mimics the effect of MSCs in reducing lung inflammation and injury. The primary goal of this study was to compare the effectiveness of intratracheal and intravenous administration of MSC-EVs in ameliorating LPS-induced lung injury. The secondary goal was to determine the underlying mechanisms of MSC-EVs in lung injury. Methods: EVs were harvested from adipose-derived MSCs cultured in EV-depleted medium. C57BL/6 mice were injected intratracheally with 5mg/kg LPS to induce acute lung injury, followed either by infusion of 5 x 105 adipose-derived MSCs intravenously, 50 µg of EVs intravenously, 50 µg of EVs intratracheally, or an equal volume of normal saline solution intravenously. Lungs, BAL fluid, and serum were harvested at 6, 24, and 48 h for analysis. To examine the uptake of EVs by macrophages in vitro, bone marrow-derived macrophages were incubated with PKH26-labeld EVs. PKH26 positive macrophages were determined via time-lapsed imaging. To determine the underlying mechanisms of EVs on macrophages, EVs were incubated with macrophages and studied for LPS-induced phenotype expression and MAP kinase phosphorylation. Results: EVs administered systemically and intratracheally were equally effective in reducing lung inflammation, bronchoalveolar protein leakage, neutrophil infiltration, and inflammatory cytokine response. Both routes of EV administration also promoted M2 macrophage polarization in the brochoalveolar lavage. EVs were efficiently taken up by macrophages and induced M2 phenotype in vitro. Furthermore, EVs reduced LPS-induced JNK activation in macrophages. Conclusion: EVs, whether administered systemically or intratracheally, mimic the effects of MSCs in mitigating acute lung injury. EVs favor M2 macrophage polarization which we speculate it may be mediated by JNK inhibition.
Author Block: J. Wang1, R. Huang1, G. Zheng2, G. Qiu2, M. Ge2, Q. Xu3, Q. Shu1, J. Xu2; 1The Children’s Hospital of Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, China, 2Shaoxing Second Hospital, 123 Yanan Road, Shaoxing,Zhejiang, China, 3Zhejiang University School of Medicine,, Hangzhou, Zhejiang, Hangzhou, China.
Rationale: Several studies have demonstrated that administration of mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) either intratracheally or systemically mimics the effect of MSCs in reducing lung inflammation and injury. The primary goal of this study was to compare the effectiveness of intratracheal and intravenous administration of MSC-EVs in ameliorating LPS-induced lung injury. The secondary goal was to determine the underlying mechanisms of MSC-EVs in lung injury. Methods: EVs were harvested from adipose-derived MSCs cultured in EV-depleted medium. C57BL/6 mice were injected intratracheally with 5mg/kg LPS to induce acute lung injury, followed either by infusion of 5 x 105 adipose-derived MSCs intravenously, 50 µg of EVs intravenously, 50 µg of EVs intratracheally, or an equal volume of normal saline solution intravenously. Lungs, BAL fluid, and serum were harvested at 6, 24, and 48 h for analysis. To examine the uptake of EVs by macrophages in vitro, bone marrow-derived macrophages were incubated with PKH26-labeld EVs. PKH26 positive macrophages were determined via time-lapsed imaging. To determine the underlying mechanisms of EVs on macrophages, EVs were incubated with macrophages and studied for LPS-induced phenotype expression and MAP kinase phosphorylation. Results: EVs administered systemically and intratracheally were equally effective in reducing lung inflammation, bronchoalveolar protein leakage, neutrophil infiltration, and inflammatory cytokine response. Both routes of EV administration also promoted M2 macrophage polarization in the brochoalveolar lavage. EVs were efficiently taken up by macrophages and induced M2 phenotype in vitro. Furthermore, EVs reduced LPS-induced JNK activation in macrophages. Conclusion: EVs, whether administered systemically or intratracheally, mimic the effects of MSCs in mitigating acute lung injury. EVs favor M2 macrophage polarization which we speculate it may be mediated by JNK inhibition.
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