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Mesenchymal stem cells (MSCs), as one of the main types of stem cells, are widely utilized in cardiac repair. However, due to their low engraftment rate within the ischemic myocardium, MSCs therapy has left much to be explored. Our previous studies found that the combination of loading dose of atorvastatin (ATV) and single injection of ATV-pretreated MSCs at 1 week after acute myocardial infarction (AMI) can promote the engraftment of MSCs and enhance the cardiac performance in AMI rats to a degree. The aim of this study was to investigate whether the combination of loading dose of ATV and repeated ATV-pretreated MSCs injections in different stages of AMI have greater efficacy than single injection.
180 female Sprague-Dawley rats were randomized into 11 groups, including Sham, AMI control; Early-1 (single injection in early stage at day 3), Early-2 (dual injections in early stage at day 3 and day 7), Early-3 (triple injections in early stage at day 1, day 3 and day 7); Mid-1 (single injection in mid-term stage at day 7), Mid-2 (dual injections in mid-term stage at day 7 and day 11), Mid-3 (triple injections in mid-term stage at day 7, day 11 and day 14); Late-1 (single injection in late stage at day 21), Late-2 (dual injections in late stage at day 21 and day 25), and Late-3 (triple injections in late stage at day 21, day 25 and day 28). Myocardial infarction was created by left anterior descending (LAD)ligation. All groups except Sham and AMI control were giving loading dose of ATV every day. ATV-pretreated MSCs labeled with CM-Dil were intravenous injected and the time point and times of infusion were listed in the parentheses above. At 5th week after AMI, cardiac functions were assessed using echocardiography and left heart catheter pressure measurement. Recruitment of MSCs to the infarcted heart, inflammatory cells and fibrosis were evaluated with histopathology.
Compared to AMI control group, cardiac performance was improved in all nine experiment groups with an increased left ventricular ejection fraction (LVEF) and decreased infarct area. In the early and mid-term stage, both LVEF and infract area of groups undergoing multiple injections of ATV-pretreated MSCs were more favorable than that of single injection, which demonstrated a cumulative effect. There were, however, no significant differences between the either two groups in the late stage. The optimal treatment group was Mid-3, with highest LVEF (baseline LVEF: 50.2±17.9%; endpoint LVEF: 65.9±10.0%) at the endpoint. The infarct area of Mid-3 group was just one third of AMI control group. In contrast, among the nine experiment groups, Early-1 group had the least improvement both in LVEF and infarct area.
On the basis of loading dose of ATV, repeated injections of ATV-pretreated MSCs did demonstrate better efficacy than single injection. And the optimal timing of repeated stem cell transplantation was from 7 days to 14 days after myocardial infarction. This study has provided preclinical evidence for repeated stem cell transplantation therapy of acute myocardial infarction.