Abstract 3545: Cytoprotective Actions of Mesenchymal Stem Cell Therapy After Acute Myocardial Infarction
Introduction: Mesenchymal cells (MSCs) have diverse effects that contribute to improved cardiac function and reduced MI size following acute myocardial infarction (MI). In addition to antibibrotic and regenerative effects, we hypothesized that MSC therapy activates molecular pathways that exert cytoprotection of endogenous adult cellular elements that potentiate endogenous cardiac repair.
Methods: Accordingly, we randomized female pigs(n=27) to receive intramyocardial injections of syngeneic porcine MSCs or placebo 3 days after MI. Animals were sacrificed at day 3, 14, and 60 post-injection. The degree of adult cardiomyocyte apoptosis and cardiomyocyte entry into the cell cycle were determined by using the fluorescent staining for TUNEL, and intranuclear Ki-67. Gene expression analysis was performed, using the Porcine Genome Array (Affymetrix) at day 3 and 14 to assess the impact of of MSC therapy on the activation of pathways involved in cardiac repair after myocardial injury.
Results: Cardiomyocyte apoptosis in the zone remote from infarction was significantly reduced in the MSC treated animals at 8weeks (0.6±0.05/mm2 placebo vs. 0.2±0.1/mm2, p<0.001), while the rate of cardiomyocyte entry into the cell cycle was significantly increased in the infarct border zone soon after delivery of the cells at day 3 (2.3±1.8/mm2 placebo vs. 21±8, P<0.05). Microarray data revealed that at day 3, there were 56 significantly changed genes in treated animals (n=3) compared with placebo (n=6) [q<0.05, fold change >3]; and at day 14, there were 245 significantly changed genes in treated pigs (n=3) compared with placebo (n=5) [q<0.05, fold change >3]. Importantly, the pathways with greatest downregulation included the TGF B1, CASP2, and Insulin-like Growth Factor Binding Protein 3(IGF BP3).
Conclusion: These findings demonstrate that MSCs have cytoprotective effects and potentiate endogenous repair mechanisms. MSC therapy activates sustained anti-apoptotic and and anti-inflammatory effects that contribute to adult myocyte survival and entry into the cell cycle.