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

Cell Stress Chaperones. 2015 Nov;20(6):979-89. doi: 10.1007/s12192-015-0627-7. Epub 2015 Aug 5.

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.

Keywords: Emphysema; Hsp70 promoter; Mouse model; Resveratrol; Stem cell-based gene therapy; VEGFA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Emphysema / drug therapy*
  • Emphysema / metabolism
  • Female
  • HSP70 Heat-Shock Proteins / genetics*
  • Lung / drug effects
  • Lung / metabolism
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Elastase / pharmacology*
  • Resveratrol
  • Smoke / adverse effects
  • Stilbenes / pharmacology*
  • Stilbenes / therapeutic use*
  • Tobacco / adverse effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • HSP70 Heat-Shock Proteins
  • Smoke
  • Stilbenes
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Pancreatic Elastase
  • Resveratrol