Abstract
Intramyocardial injection of adipose-derived stem cells (ASC) with other cell types in acute myocardial infarction (AMI) animal models has consistently shown promising clinical regenerative capacities. We investigated the effects of intramyocardial injections of mouse ASC (mASC) with mouse endothelial cells (mEC) on left ventricular function and generation of pericardial fat in AMI rats. AMI rat models were created by ligating left anterior descending coronary artery and were randomly assigned into four groups: control (n = 10), mASC (n = 10), mEC (n = 10) and mASC+mEC (n = 10) via direct intramyocardial injections, and each rat received 1x106 cells around three peri-infarct areas. Echocardiography and cardiac positron emission tomography (PET) were compared at baseline and on 28 days after AMI. Changes in left ventricular ejection fraction measured by PET, increased significantly in mASC and mASC+mEC groups compared to mEC and control groups. Furthermore, significant decreases in fibrosis were confirmed after sacrifice on 28 days in mASC and mASC+mEC groups. Successful cell engraftment was confirmed by positive Y-Chromosome staining in the transplantation region. Pericardial fat increased significantly in mASC and mASC+mEC groups compared to control group, and pericardial fat was shown to originate from the AMI rat. mASC group expressed higher adiponectin and lower leptin levels in plasma than control group. In addition, pericardial fat from AMI rats demonstrated increased phospho-AMPK levels and reduced phospho-ACC levels. Intramyocardial mASC transplantation after AMI in rats increased pericardial fat, which might play a protective role in the recovery of myocardial function after ischemic myocardial damage.
Highlights
Ischemic cardiac diseases such as acute myocardial infarction (AMI) are a leading cause of death worldwide
The cellular characteristics of mouse ASC (mASC) and mouse endothelial cells (mEC) were studied by fluorescence immunostaining, and positive surface antigen expressions of CD31, CD34, CD106, and Sca-1 were confirmed. mASC were positive for CD34, CD106, and Sca-1, and mEC were positive for CD31, CD106, and Sca-1 (Fig 1A)
Adipogenic, osteogenic, endothelial, and cardiomyogenic differentiation of mASC were confirmed by Oil Red O, Alizarin Red S staining, Flk1, α-actinin and cardiac troponin T expression, respectively (Fig 1C). mASC exhibited significantly higher endothelial (CD31 and CD144; 8.71-fold and 2.10-fold) and cardiomyogenic differentiation potentials compared to undifferentiated mASC (Fig 1D)
Summary
Ischemic cardiac diseases such as acute myocardial infarction (AMI) are a leading cause of death worldwide. Inducing recovery of damaged myocardium has become an important therapeutic goal for treating AMI patients. Stem cell transplantation therapy has been used to treat failing hearts for more than a decade, and a large number of studies have provided profound evidence that implanted cells can participate in generation of new tissue to mechanically and biochemically support the damaged heart and enhance its function [1, 2]. Several studies using various types of stem cells have shown promising results in halting myocardial damage and improving LV function [3, 4]. A number of preclinical studies have demonstrated treatment of damaged myocardium with ASC in combination with other cell types in order to maximize efficacy, and implanting ASC with endothelial cells (EC) provides efficient blood supply through formation of vasculature [6]
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