Stem cells (Dayton, Ohio), 2017-07, Vol.35 (7), p.1849-1859
2017
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- Autor(en) / Beteiligte
- Titel
- Mesenchymal Stem Cell Microvesicles Attenuate Acute Lung Injury in Mice Partly Mediated by Ang‐1 mRNA
- Ist Teil von
- Stem cells (Dayton, Ohio), 2017-07, Vol.35 (7), p.1849-1859
- Ort / Verlag
- United States: Oxford University Press
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Microvesicles (MVs) derived from human mesenchymal stem cells (MSC MVs) were demonstrated to ameliorate inflammation in lungs. We have found their content of mRNA for keratinocyte growth factor was partly involved in their therapeutic effects. As MSC MVs also contained a substantial quantity of angiopoietin‐1 (Ang‐1) mRNA, which plays an essential role in vascular stabilization and resolving inflammation, we hypothesized that Ang‐1 mRNA might similarly account for a part of their therapeutic effects. We downregulated Ang‐1 mRNA expression in MVs, using a lentivirus vector carrying Ang‐1 short hairpin RNA to transfect MSCs. A mouse model of lipopolysaccharide induced acute lung injury (ALI) was used in vivo. We also studied in vitro interactions between Ang‐1 mRNA deficient MVs on macrophages and human lung microvascular endothelial cells. Compared with negative control, Ang‐1 mRNA deficient MVs increased the influx of neutrophils and macrophage inflammatory protein‐2 levels in bronchoalveolar lavage fluid by 136% and 105%, respectively, suggesting a deteriorative lung inflammation and a failure to restore pulmonary capillary permeability assessed by Evan's blue dye and bronchoalveolar lavage albumin level. In vitro, the addition of Ang‐1 mRNA deficient MVs failed to maintain the integrity of endotoxin‐stimulated microvascular endothelial cells and abrogated the decrease in tumor necrosis factor‐α level and the increase in interleukin‐10 level mediated by negative control in RAW 264.7 cells. In summary, the therapeutic effects of MVs in ALI, and their immunomodulatory properties on macrophages were partly mediated through their content of Ang‐1 mRNA. Stem Cells 2017;35:1849–1859 MSC MVs improved lung injury as assessed by histology at 48 hours. H&E staining of lung section demonstrated a reduction in inflammatory cell influx, blood, edema, airspace congestion, and wall thickening (scale bars = 200μm). Ang‐1 SiRNA MSC MV significantly eliminated the beneficial effects of MSC MVs.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1066-5099eISSN: 1549-4918DOI: 10.1002/stem.2619Titel-ID: cdi_proquest_miscellaneous_1884464580
- Format
- –
- Schlagworte
- Acute Lung Injury - chemically induced, Acute Lung Injury - genetics, Acute Lung Injury - pathology, Acute Lung Injury - prevention & control, Albumin, Alveoli, Angiopoietin, Angiopoietin-1 - antagonists & inhibitors, Angiopoietin-1 - genetics, Angiopoietin-1 - metabolism, Animal models, Animals, Attenuation, Bronchoalveolar Lavage Fluid - chemistry, Bronchus, Capillary Permeability - genetics, Cell-Derived Microparticles - chemistry, Cell-Derived Microparticles - secretion, Cell-Derived Microparticles - transplantation, Chemokine CXCL2 - genetics, Chemokine CXCL2 - metabolism, Disease Models, Animal, Endothelial cell, Endothelial cells, Endothelial Cells - cytology, Endothelial Cells - metabolism, Gene expression, Gene Expression Regulation, Humans, Immunomodulation, In vitro methods and tests, Inflammation, Integrity, Interleukin 10, Interleukin-10 - genetics, Interleukin-10 - metabolism, Keratinocyte growth factor, Lentiviral vector, Leukocytes (neutrophilic), Lipopolysaccharides, Lung, Lung - metabolism, Lung - pathology, Lungs, Macrophage inflammatory protein, Macrophages, Male, Membrane permeability, Mesenchymal stem cell, Mesenchymal Stromal Cells - cytology, Mesenchymal Stromal Cells - secretion, Mesenchyme, Mice, Mice, Inbred C57BL, Microvasculature, Neutrophil Infiltration - genetics, Neutrophils - metabolism, Neutrophils - pathology, Permeability, Primary Cell Culture, Ribonucleic acid, RNA, RNA, Messenger - antagonists & inhibitors, RNA, Messenger - genetics, RNA, Messenger - metabolism, RNA, Small Interfering - genetics, RNA, Small Interfering - metabolism, Rodents, Signal Transduction, Stabilization, Stem cell transplantation, Stem cells, Tumor necrosis factor, Tumor Necrosis Factor-alpha - genetics, Tumor Necrosis Factor-alpha - metabolism