title: Mesenchymal Stem Cell Microvesicles Attenuate Acute Lung Injury in Mice Partly Mediated by Ang-1 mRNA.
abstract: 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.
authors.affiliation: Department of Pulmonary disease, Huadong Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Tang
authors.affiliation: Department of Pulmonary disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Shi
authors.affiliation: La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, University Pierre and Marie Curie (UPMC), Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Monsel
authors.affiliation: Department of Pulmonary disease, Huadong Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Pulmonary disease, Huadong Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Hui-Li
authors.initials: HL
authors.lastname: Zhu
authors.affiliation: Department of Pulmonary disease, Huadong Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Ying-Gang
authors.identifier: 0000-0001-7416-548X
authors.initials: YG
authors.lastname: Zhu
authors.affiliation: Ruijin Hospital, Medical School of Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors.forename: Jie-Ming
authors.initials: JM
authors.lastname: Qu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000235:genetics; D055252:Cell-Derived Microparticles / Q000737:chemistry / Q000378:metabolism* / Q000637:transplantation; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000235:genetics; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10
keywords: Animal models; Endothelial cell; Lentiviral vector; Lung; Mesenchymal stem cell