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.

Induced Pluripotent Stem Cells Attenuate Endothelial Leakage in Acute Lung Injury via Tissue Inhibitor of Metalloproteinases-1 to Reduce Focal Adhesion Kinase Activity

“…Angiopoietin-1 is an angiogenic growth factor that promotes the generation of stable and functional vasculature. Previous studies have demonstrated that angiopoietin-1 plays a crucial role in MSC therapy for ALI/ARDS [39,40]. In this study, we did not detect the level of angiopoietin-1 in the iPSC-CM and MEF-CM.…”

Mesenchymal Stem Cell Microvesicles Restore Protein Permeability Across Primary Cultures of Injured Human Lung Microvascular Endothelial Cells

“…We also previously found that the secretion of Ang1 by MSCs was critical in restoring fluid transport across primary culture of human alveolar epithelial type II cells . More recently, Tang et al found that Ang1 in MSC MV was important in reducing inflammation and pulmonary edema in LPS induced ALI in mice. In the current study, we found that Ang1 gene expression in cytomix‐injured HLMVEC was significantly increased at 6 and 12 hours and Ang1 protein secretion was significantly increased at 6 hours following MSC MV treatment.…”

Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19

“…Containing a panoply of chemokines, growth factors, mRNA, and microRNA with antiinflammatory, regenerative, and immunomodulatory functions, exosomes are the paracrine and endocrine mediators that confer bmMSCs with their healing properties, a fact that taken together with their superior safety profile, stability, and scalability, makes exosomes a tantalizing, practical, and yet unexplored treatment option for COVID-19 [15][16][17][18]. Multiple preclinical studies have shown favorable therapeutic effects of bone marrow-derived exosomes delivered intravenously in animal models of acute lung injury, ARDS, asthma, and other inflammatory diseases, with analyses revealing reduced alveolar inflammation, enhanced edema clearance, restoration of leaky epithelial membranes, and other sequelae of cytokine storm [19][20][21][22][23][24].…”