title: Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model.
abstract: 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.
authors.affiliation: Institute of Biotechnology, College of Bioresources and Agriculture, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Young-Bin
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biomedical Sciences, Division of Biotechnology, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Lan
authors.affiliation: Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi, 600, Taiwan, Republic of China.
authors.forename: Lih-Geeng
authors.initials: LG
authors.lastname: Chen
authors.affiliation: Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
authors.forename: Tsung-Teng
authors.initials: TT
authors.lastname: Huang
authors.affiliation: Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
authors.forename: Kong-Bung
authors.initials: KB
authors.lastname: Choo
authors.affiliation: Department of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan, Republic of China.
authors.forename: Winston T K
authors.initials: WT
authors.lastname: Cheng
authors.affiliation: Institute of Biotechnology, College of Bioresources and Agriculture, National Taiwan University, Taipei, Taiwan, Republic of China. benlee@ntu.edu.tw.|Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicne, Taipei, Taiwan, Republic of China. benlee@ntu.edu.tw.
authors.forename: Hsuan-Shu
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Graduate Institute of Biomedical Sciences, Division of Biotechnology, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. kchong@mail.cgu.edu.tw.|Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. kchong@mail.cgu.edu.tw.|Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. kchong@mail.cgu.edu.tw.|Department of Family Medicine, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan, Republic of China. kchong@mail.cgu.edu.tw.
authors.forename: Kowit-Yu
authors.initials: KY
authors.lastname: Chong
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004646:Emphysema / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase / Q000494:pharmacology*; D000077185:Resveratrol; D012906:Smoke / Q000009:adverse effects; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use*; D014026:Nicotiana / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D012906:Smoke; D013267:Stilbenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D010196:Pancreatic Elastase; D000077185:Resveratrol
keywords: Emphysema; Hsp70 promoter; Mouse model; Resveratrol; Stem cell-based gene therapy; VEGFA