Yonsei Med J.  2017 Jan;58(1):206-216. 10.3349/ymj.2017.58.1.206.

Angiopoietin-1 Modified Human Umbilical Cord Mesenchymal Stem Cell Therapy for Endotoxin-Induced Acute Lung Injury in Rats

• Huang ZW
• Liu N
• Li D
• Zhang HY
• Wang Y
• Liu Y
• Zhang LL
• Ju XL

• KMID: 2374208
• DOI: http://doi.org/10.3349/ymj.2017.58.1.206

Abstract

PURPOSE
Angiopoietin-1 (Ang1) is a critical factor for vascular stabilization and endothelial survival via inhibition of endothelial permeability and leukocyte- endothelium interactions. Hence, we hypothesized that treatment with umbilical cord mesenchymal stem cells (UCMSCs) carrying the Ang1 gene (UCMSCs-Ang1) might be a potential approach for acute lung injury (ALI) induced by lipopolysaccharide (LPS).
MATERIALS AND METHODS
UCMSCs with or without transfection with the human Ang1 gene were delivered intravenously into rats one hour after intra-abdominal instillation of LPS to induce ALI. After the rats were sacrificed at 6 hours, 24 hours, 48 hours, 8 days, and 15 days post-injection of LPS, the serum, the lung tissues, and bronchoalveolar lavage fluid (BALF) were harvested for analysis, respectively.
RESULTS
Administration of fluorescence microscope confirmed the increased presence of UCMSCs in the injured lungs. The evaluation of UCMSCs and UCMSCs-Ang1 actions revealed that Ang1 overexpression further decreased the levels of the pro-inflammatory cytokines TNF-α, TGF-β1, and IL-6 and increased the expression of the anti-inflammatory cytokine IL-10 in the injured lungs. This synergy caused a substantial decrease in lung airspace inflammation and vascular leakage, characterized by significant reductions in wet/dry ratio, differential neutrophil counts, myeloperoxidase activity, and BALF. The rats treated by UCMSCs-Ang1 showed improved survival and lower ALI scores.
CONCLUSION
UCMSCs-Ang1 could improve both systemic inflammation and alveolar permeability in ALI. UC-derived MSCs-based Ang1 gene therapy may be developed as a potential novel strategy for the treatment of ALI.

Keyword

Angiopoietin-1; human umbilical cord mesenchymal stem cell; acute lung injury

MeSH Terms

Acute Lung Injury/chemically induced/*therapy
Angiopoietin-1/*genetics
Animals
Bronchoalveolar Lavage Fluid
Cytokines/metabolism
Endotoxins
Genetic Therapy
Interleukin-10/metabolism
Interleukin-6/metabolism
Leukocyte Count
Lipopolysaccharides
Lung/metabolism
Male
*Mesenchymal Stem Cell Transplantation
Mesenchymal Stromal Cells/metabolism
Neutrophils/metabolism
Rats
Transforming Growth Factor beta1/metabolism
Tumor Necrosis Factor-alpha/metabolism
Umbilical Cord/*cytology
Angiopoietin-1
Cytokines
Endotoxins
Interleukin-10
Interleukin-6
Lipopolysaccharides
Transforming Growth Factor beta1
Tumor Necrosis Factor-alpha