Mesenchymal stem cell‐based angiopoietin‐1 gene therapy for acute lung injury induced by lipopolysaccharide in mice

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) can serve as a vehicle for gene therapy. Angiopoietin-1 (Ang1) is a critical factor for endothelial survival and vascular stabilization via the inhibition of endothelial permeability and leukocyte-endothelium interactions. We hypothesized that MSC-based Ang1 gene therapy might be a potential therapeutic approach for lipopolysaccharide (LPS)-induced lung injury. MSCs were isolated from 6 week-old inbred male mice and transduced with the Ang1 gene, using a lentivirus vector. The MSCs showed no significant phenotypic changes after transduction. In the in vivo mouse model, the LPS-induced lung injury was markedly alleviated in the group treated with MSCs carrying Ang1 (MSCs-Ang1), compared with groups treated with MSCs or Ang1 alone. The expression of Ang1 protein in the recipient lungs was increased after MSCs-Ang1 administration. The histopathological and biochemical indices of LPS-induced lung injury were improved after MSCs-based Ang1 gene treatment. MSCs-Ang1 administration also reduced pulmonary vascular endothelial permeability and the recruitment of inflammatory cells into the lung. Cells of MSC origin could be detected in the recipient lungs for 2 weeks after injection with MSCs. These results suggest that MSCs and Ang1 have a synergistic role in the treatment of LPS-induced lung injury. MSC-based Ang1 gene therapy may be developed as a potential novel strategy for the treatment of acute lung injury.

Intrapleural delivery of mesenchymal stem cells: a novel potential treatment for pleural diseases

“…Unlike classical intravenous or intratracheal delivery methods [5][6][7][8][9] , intrapleurally delivered MSCs were found to be distributed only to the pleurae and the pleural cavity, providing a promising cell-based therapeutic strategy for primary and secondary pleural diseases.…”

“…Recent studies, including one of our previous studies, have demonstrated that intravenous (iv) or intratracheal (it) delivery of bone marrow-derived mesenchymal stem cells (MSCs) participates in the improvement of various experimental models of lung injury, thus demonstrating that MSCs play an important role in the treatment of animals with acute lung injury [5][6][7][8][9][10][11][12] .…”

Ventilator-Induced Lung Injury: Mechanisms and Future Therapeutic Interventions

“…In this regard, intravenous MSC administration reduced lung inflammation and prolonged survival in a murine model of bleomycin-induced lung injury and fibrosis (Ortiz et al, 2003;Rojas et al, 2005). Similar effects of MSC treatment have been described in murine models of endotoxin-induced lung injury Xu et al, 2007;Xu et al, 2008). Xu et al observed that intravenous MSC administration prevents endotoxin-induced lung injury, edema formation and inflammation in mice (Xu et al, 2007).…”

“…Xu et al observed that intravenous MSC administration prevents endotoxin-induced lung injury, edema formation and inflammation in mice (Xu et al, 2007). Moreover, genetic engineering of MSCs showed to improve the protective effects of MSCs even more Xu et al, 2008). Mei et al evaluated the integrity of the alveolarcapillary membrane barrier by measuring total protein, albumin and IgM concentration in BALf in a murine model of LPS-induced ALI .…”

Cell Therapy in Chronic Obstructive Pulmonary Disease: State of the Art and Perspectives

“…So, the results obtained and reported have been evaluated more carefully by some authors, who challenge the accuracy of the employed detection techniques. For example, after transplanting MSC GFP + in mice which had previously received an LPS intraperitoneal injection, Xu et al (2008) did not find, in the immunohistochemistry analysis of the pulmonary tissue conducted 14 days after the transplant, circumstantial evidence for a significant presence of cells with positive sign of GFP. However, although the authors did not find evidence for an actual integration of MSC to the pulmonary tissue and the presence of cells with the pulmonary phenotype, there was demonstration that the SC transplant afforded a decrease in the lungs inflammation and edema induced by the LPS.…”