Abstract 3014: Pharmacologically Preconditioned MSCs Induce Myocardial Angiogenesis, Resuscitate Myocardial Integrity and Reduce Ventricular Remodeling in the Infarcted Rat Myocardium
Mounting evidence supports the therapeutic potential of mesenchymal stem cells (MSC) in the repair and resuscitation of scarred myocardium during IHDs. However, apprehensions exist with respect to poor viability of transplanted MSCs in the infarcted cardiac microenvironment. Here, we have delved a novel strategy of pharmacological-preconditioning (PC) the MSCs with cytoprotective phytoalexin resveratrol (RSV) prior to intramyocardial delivery, to enhance their therapeutic potential. RSV-PC MSCs (25μM; 24h) revealed increased survivability, proliferation (Ki67 index/microtubule assembly), tuburogenesis and elevated VEGF, HO-1 (stress resistance), CXCR4 (mobilization), CyclinE2 (cell-cycle) and Sirt1 (longevity) levels in vitro. Therefore, we evaluated the reparative potential of RSV-PC MSCs as compared to naïve MSCs in rat myocardial infarction (MI) model. Rats were randomized into Control Sham (CS), MI+PBS (CMI), MI + MSC (MMI) & MI + RSV-MSC (MRMI) groups. After 7d of MI induction (permanent LAD ligation), PBS, 2x105 naïve MSCs or RSV-PC MSCs were administered intramyocardially at 4 sites around the infarct border-zone. PKH-26 labeled MSC transplantation was used to validate successful engraftment. We observed increased capillary density (3013±86 vs 2575±60, counts/mm2), Ki67+ cardiomyocytes (CM) and Cx43+ CM-CM gap-junctions in the infarct border-zone after 4d, and increased arteriolar density at 7d (7.0±0.5 vs 4.4±0.9, counts/ mm2) with a consequent reduction in cardiac fibrosis at 7d (4.6±0.6 vs 9.6±0.1, %) & 150d (2.1±0.9 vs 6.6±0.8, %) post-treatment respectively, in the MRMI group vs MMI. Immunoblot analysis unveiled increased cTnT, αSMA, CD31, Cx43, CXCR4, CyclinE2 and Sirt1 at 4d & 7d following PC-MSC transplantation vs naïve MSCs. These molecular events resulted in decreased LVIDs (5.3±0.2 vs 6.1±0.04, mm), increased EF (63.9±0.4 vs 57.4±0.9, %) & FS (36.2±0.3 vs 31.6±0.6, %), causing a significant reduction in ventricular remodeling after 150d in the MRMI group compared to MMI. Our preclinical data demonstrates that RSV-PC enhances the capacity of MSCs to repair the infarcted myocardium and houses a potential for development as a therapeutic strategy against the myocardial damage caused by ischemic cardiomyopathies.