Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction

Abstract

Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV‐pretreated mesenchymal stem cells (MSCs) (ATV‐MSCs) at 1 week post‐acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of ATV‐MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to determine the optimal time window for MSC treatment, we first assessed stromal cell‐derived factor‐1 (SDF‐1) dynamic expression and inflammation. Next, we compared MSC recruitment and differentiation, cardiac function, infarct size, and angiogenesis among animal groups with single, dual, and triple injections of ATV‐MSCs at early (Early1, Early2, Early3), mid‐term (Mid1, Mid2, Mid3), and late (Late1, Late2, Late3) stages. Compared with AMI control, intensive ATV significantly augmented SDF‐1 expression 1.5∼2.6‐fold in peri‐infarcted region with inhibited inflammation. ATV‐MSCs implantation with ATV administration further enhanced MSC recruitment rate by 3.9%∼24.0%, improved left ventricular ejection fraction (LVEF) by 2.0%∼16.2%, and reduced infarct size in all groups 6 weeks post‐AMI with most prominent improvement in mid groups and still effective in late groups. Mechanistically, ATV‐MSCs remarkably suppressed inflammation and apoptosis while increasing angiogenesis. Furthermore, triple injections of ATV‐MSCs were much more effective than single administration during early and mid‐term stages of AMI with the best effects in Mid3 group. We conclude that the optimal strategy is multiple injections of ATV‐MSCs combined with intensive ATV administration at mid‐term stage of AMI. The translational potential of this strategy is clinically promising. Stem Cells Translational Medicine 2019;8:1068–1083

High Frequency of Intravenous Injection of Human Adipose Stem Cell Conditioned Medium Improved Embryo Development of Mice in Advanced Maternal Age through Antioxidant Effects

“…For instance, a double injection of human MSCs increased the survival of injected cells and their paracrine effects in a critical limb ischemia mouse model when compared to a single injection containing the same dosage of cells [48]. A study on an acute myocardial infarction rat model also indicated that multiple injections of rat MSCs had greater efficacy than single administration [49]. It is consistent with our results that the expression levels of gpx1 and catalase in ovaries was significantly enhanced in the group treated with a high frequency of ASC-CM injection regardless of their age.…”

GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing

“…However, little is known about the physiological functions of GDF11 in mesenchymal stromal cells (MSCs), which possess mesenchymal stromal characteristics with classic mesenchymal stromal markers. Recent research showed that MSCs play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions 4‐6 . However, therapeutic effect on myocardial infarction by MSCs is limited due to the poor survival rate given a hostile microenvironment in an ischemic heart.…”

Adiponectin Improves Therapeutic Efficacy of Mesenchymal Stem Cells by Enhancing Their Engraftment and Survival in Peri-infarct Myocardium Through AMPK Pathway

“…Isolation and culture of adult rat bone marrow MSCs were performed as previously described [20]. In brief, bone marrow was harvested from the tibia and femur of Sprague-Dawley rats (60-80g, male) and plated into cell culture flasks with complete medium in an incubator set at 37 °C containing 5%…”