부산대학교 도서관

Introduction: We have demonstrated that neonatal mesenchymal stem cells (nMSCs) extracted from human neonatal cardiac tissues and their exosomes, secretome, potently decrease cardiac fibrosis and improve cardiac function in the rat model of myocardial infarction. CD4CD25Foxp3 (forkhead box 3) regulatory T cells (Tregs) are recently shown to regulate the formation of cardiac fibrosis in myocardial infarction. How nMSCs and secretome affect cardiac fibrosis and Tregs of animals with heart failure with preserved ejection fraction (HFpEF) is unknown.Hypothesis: We hypothesized that nMSCs and secretome ameliorate cardiac fibrosis and diastolic dysfunction in HFpEF by regulating cardiac Tregs.Methods: C57BL/6 mice were fed 60% high-fat diet and L-NAME to induce HFpEF or normal chow as a control. Left ventricular morphology and function were evaluated using an echocardiography. After the mice developed HFpEF, the animals were injected 10 nMSCs, 10 mg/kg of secretome, or equivalent amounts of vehicle as a control via tail vein. Myocardial fibrosis was quantified in trichrome-stained heart sections. Circulating and cardiac Tregs were measured on a FACSCanto II cytometer. Fingolimod at a dose of 3 mg/kg was intraperitoneally injected daily for 18 days.Results: C57BL/6 mice fed high-fat diet and L-NAME for 5 weeks developed obesity, myocardial fibrosis, left ventricular hypertrophy and diastolic dysfunction (increases in mitral E/e’ ratio), and exercise intolerance with > 50% of left ventricular ejection fraction. Compared to the HFpEF mice receiving vehicle, either nMSCs or secretome significantly decreased cardiac interstitial fibrosis and mitral E/e’ ratio and increased cardiac CD4CD25FoxP3 Tregs from 1 to 4 weeks post treatment. Importantly, either nMSCs or secretome enhanced the exercise speed and distance of the HFpEF mice. Fingolimod significantly decreased circulating and cardiac Tregs in the HFpEF mice, which blocked the beneficial effects of nMSCs and secretome on cardiac fibrosis and diastolic function.Conclusions: nMSCs and secretome ameliorate cardiac fibrosis and diastolic dysfunction by expanding CD4CD25FoxP3 Tregs in HFpEF. These results suggest that nMSCS and secretome have high therapeutic potential for HFpEF.