Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model

• Published in: Cell stress & chaperones 2015-11, Vol.20 (6), p.979-989
• Main Authors: Chen, Young-Bin, Lan, Ying-Wei, Chen, Lih-Geeng, Huang, Tsung-Teng, Choo, Kong-Bung, Cheng, Winston T. K., Lee, Hsuan-Shu, Chong, Kowit-Yu
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Cell lines; Cell Survival - drug effects; Cells, Cultured; Chronic obstructive pulmonary disease; Cigarette smoking; Cigarettes; Disease Models, Animal; Emphysema; Emphysema - drug therapy; Emphysema - metabolism; Epithelial cells; Female; HSP70 Heat-Shock Proteins - genetics; Immunology; Lung - drug effects; Lung - metabolism; Lungs; Mesenchymal stem cells; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Messenger RNA; Mice; Mice, Inbred C57BL; Neurosciences; Nicotiana - adverse effects; Original Paper; Pancreatic Elastase - pharmacology; Pulmonary alveoli; Resveratrol; Smoke - adverse effects; Stilbenes - pharmacology; Stilbenes - therapeutic use; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1355-8145; 1466-1268
• DOI: 10.1007/s12192-015-0627-7

Chronic obstructive pulmonary disease (COPD) is a sustained blockage of the airways due to lung inflammation occurring with chronic bronchitis and/or emphysema. Progression of emphysema may be slowed by vascular endothelial growth factor A (VEGFA), which reduces apoptotic tissue depletion. Previously, authors of the present report demonstrated that cis-resveratrol (c-RSV)-induced heat-shock protein 70 (HSP70) promoter-regulated VEGFA expression promoted neovascularization of genetically modified mesenchymal stem cells (HSP-VEGFA-MSC) in a mouse model of ischemic disease. Here, this same stem cell line was evaluated for its protective capacity to alleviate elastase-induced pulmonary emphysema in mice. Results of this study showed that c-RSV-treatment of HSP-VEGFA-MSC exhibited synergy between HSP70 transcription activity and induced expression of anti-oxidant-related genes when challenged by cigarette smoke extracts. Eight weeks after jugular vein injection of HSP-VEGFA-MSC into mice with elastase-induced pulmonary emphysema followed by c-RSV treatment to induce transgene expression, significant improvement was observed in respiratory functions. Expression of VEGFA, endogenous nuclear factor erythroid 2-related factor (Nrf 2), and manganese superoxide dismutase (MnSOD) was significantly increased in the lung tissues of the c-RSV-treated mice. Histopathologic examination of treated mice revealed gradual but significant abatement of emphysema and restoration of airspace volume. In conclusion, the present investigation demonstrates that c-RSV-regulated VEGFA expression in HSP-VEGFA-MSC significantly improved the therapeutic effects on the treatment of COPD in the mouse, possibly avoiding side effects associated with constitutive VEGFA expression.