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.

Preclinical Studies of Mesenchymal Stem Cell (MSC) Administration in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review and Meta-Analysis

“…The full-text articles were independently assessed by all three authors. Twenty one articles were included in the systematic review and meta-analysis, as shown in Table 1 , including studies of human bone marrow MSC (BM-MSC, n = 1), human adipose stromal cells (ASC, n = 1), human cord blood derived MSC (n = 1) or human tubal MSC (n = 1) [ 21 – 24 ], rat BM-MSC (n = 7) [ 9 , 25 – 30 ], rabbit bone marrow derived mesenchymal stem cells (n = 1) [ 31 ], rat adipose derived stromal cells (n = 2) [ 32 , 33 ], guinea pig adipose derived MSCs (n = 2) [ 34 , 35 ], rat amniotic fluid derived MSC (n = 1) [ 36 ], and mice BM-MSC or adipose-derived MSC or lung tissue MSC (n = 4) [ 8 , 10 , 37 , 38 ]. Among the 21 articles 8 are from China, 4 are from Japan, 2 are from Korea, 2 are from Brazil, 2 are from Iran, one is from Canada, one from the USA, and one is from Taiwan.…”

“…In this context, studies have demonstrated that MSCs have anti-inflammatory and immune-modulatory effects in diverse types of tissue injury and allergic inflammation [ 6 , 7 ]. MSCs are now known to have potent beneficial effects in animal models of many types of lung injury including cigarette smoke-induced or elastase-induced COPD/emphysema [ 8 – 10 ], bleomycine-induced fibrosis [ 11 , 12 ], bronchopulmonary dysplasia [ 13 , 14 ], ventilator-induced lung injury [ 15 ], and bacterial pneumonia [ 16 , 17 ]. Much of these preclinical data support the therapeutic potential of MSCs in the animal models of human diseases including COPD.…”

Mesenchymal stromal cell therapy in COPD: from bench to bedside

“… 38 , 39 To avoid the complications associated with constitutive VEGFA expression, researchers have achieved conditional expression of VEGFA by MSCs under the regulation of a c -resveratrol ( c -RSV)-inducible heat shock protein (HSP)-70 promoter. 18 HSP70 concentration is increased in the serum of COPD patients and has a linear relationship with disease severity. c -RSV, a phytochemical that indirectly activates HSP70 promoter activity, induces expression of antioxidant-related genes in HSP70-VEGFA-MSCs in vitro, including nuclear factor erythroid-2-related factor (Nrf-2) and heme oxygenase-1 (HO-1).…”

“…MSCs may be harvested from several adult tissues. In emphysema models, different sources of MSCs have been tested, including adipose tissue (AD), 5 , 10 – 13 lung, 5 , 14 umbilical cord, 15 human tubal tissue, 16 amniotic fluid, 17 and bone marrow (BM), 5 , 18 – 21 which is the most widely used source. MSCs may present different phenotypes depending on their site of origin, resulting in differences in immunogenicity, anti-inflammatory and regenerative ability, and expansibility in culture.…”

“…HSP70-VEGFA-MSCs exhibited higher survival than control MSCs in a CS extract challenge, and combined treatment with c -RSV and engraftment of HSP-VEGFA-MSCs promoted better therapeutic effects than mock control in elastase-induced emphysema: upregulation of antioxidant gene expression (Nrf-2, HO-1, and manganese-dependent superoxide dismutase) and reduced mean linear intercept. 18 …”