Cyclosporine A-nanoparticles enhance the therapeutic benefit of adipose tissue- derived stem cell transplantation in a swine myocardial infarction model

Abstract

Qiaoxiang Yin,1 Zhiyong Pei,2 Heng Wang,3 Yusheng Zhao4 1Department of Geriatric Cardiology, Chinese General Hospital of the Air Force, 2Department of Geriatric Cardiology, Beijing Military General Hospital, 3Department of Neurology, Chinese General Hospital of the Air Force, 4Institute of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, People’s Republic of China Abstract: Treatment of myocardial infarction (MI) with adipose-derived stem cells (ASCs) has produced promising results. Cyclosporine A (CsA) inhibits apoptosis by preventing the opening of mitochondrial permeability transition pores. A CsA nanoparticle emulsion (CsA-NP) has lower toxicity and higher efficiency as compared to CsA. In this study, we hypothesized that a combination of ASCs and CsA-NP would enhance the therapeutic efficiency in a swine MI model. MI was induced in pig hearts by occlusion of the left anterior descending artery. The animals that survived MI were divided into four groups and 1 week later received intracoronary ASCs (ASCs, n=6), intracoronary culture media in combination with CsA-NP (CsA-NP, n=6), intracoronary ASCs in combination with CsA-NP (ASCs + CsA-NP, n=6), or remained untreated (control, n=4). Animals were sacrificed 8 weeks later and were evaluated for cardiac function by delayed-enhanced magnetic resonance imaging and immunohistopathology. We observed that the left ventricular ejection fraction (LVEF) was significantly increased in the ASCs + CsA-NP group, compared to the CsA-NP group (53.6%±2.4% versus 48.6%±1.5%, P<0.05), and the ASCs group (53.6%±2.4% versus 48.3%±1.8%, P<0.05). More importantly, the infarct size was significantly smaller in the ASCs + CsA-NP group as compared to the CsA-NP group (6.2±1.7 cm3 versus 9.1±3.4 cm3, P<0.05) and the ASCs group (6.2±1.7 cm3 versus 7.5±0.6 cm3, P<0.05). These findings were further confirmed by analysis of the expression of cardiomyocyte markers, myosin heavy chain (α-actinin) and troponin T. In addition, the CsA-NP + ASCs treatment promoted neovascularization (P<0.05) and inhibited cardiomyocyte apoptosis (P<0.01) compared to the control group. This study demonstrates that CsA-NP enhanced the therapeutic benefits of ASCs transplantation for MI. Keywords: cyclosporine A nanoparticle emulsion, cyclosporine A, adipose tissue-derived stem cells, myocardial infarction