Abstract 155: Lin28 Enhances Cardiac Progenitor Cell Ability to Repair the Heart by Reprogramming Cellular Metabolism

Abstract

Rationale: The adult Heart is largely a dormant organ supporting limited cellular turnover. In contrast, neonatal cardiac tissue proliferates and is capable of regeneration while operating under a specialized metabolic state. During transition to adulthood, cardiac metabolism undergoes a rapid shift that coincides with termination of regenerative processes. Whether altering cardiac metabolism recapitulates regenerative potential remains untested. Recently, introduction of Lin28, a metabolic regulator of pluripotency, enhances tissue repair after injury. Nevertheless, there are no studies characterizing the effect of Lin28 on cardiac repair. Objective: Determine the effect of Lin28 on cardiac progenitor cell function and cardiac repair after injury. Methods and Results: Lin28 expression coincides during heart development with c-kit and declines postnatal with complete abrogation in 3-week-old adult heart as measured by qRT-PCR and immunohistochemistry. CPCs were engineered with Lin28-GFP (CPCLin) lentivirus GFP expressing CPCs were used as controls (CPC-G). CPCLin demonstrated increased proliferation measured by CyQuant compared to CPC-G, concurrent with decreased apoptosis. Interestingly, CPCLin demonstrated a significant increase in lactate production, pyruvate kinase activity, glucose uptake together with enhancement of glycolysis and expression of glycolytic enzymes compared to CPC-G. Oxidative metabolism was also upregulated together with increased intracellular ATP in CPCLin compared to controls. Additionally, CPCLin demonstrated significantly reduced ROS generation as measured by CM-H 2 TMROS based FACS analysis compared to CPC-G. To determine in vivo efficacy, CPCLin and CPC-G were transplanted in the heart after myocardial infarction. CPC-Lin hearts showed significant increase in cardiac structure and function 8 weeks after MI. Increased persistence and proliferation of transplanted CPC-Lin cells together with reduced apoptosis were observed in CPCLin hearts compared to control CPC-G hearts 2 days after transplantation. Conclusions: Lin28 modification of CPCs reprograms cellular metabolism in CPCs enhancing proliferation and survival including ability to repair the heart after myocardial injury.