Metabolic optimization of cell therapy

点击翻译按钮获取中文摘要

ABSTRACT Type 2 diabetes is an independent risk factor for the development of heart failure. It contributes to adverse cardiac remodeling and it increases heart failure mortality. While cell therapy offers promise for treating heart failure in nondiabetic patients, the efficacy of cell therapy in diabetic hearts remains uncertain. Our preliminary studies show that diabetes impairs cardiac progenitor cell (CPC) growth, survival and differentiation and that CPCs isolated from diabetic hearts fail to promote myocardial recovery after myocardial infarction (MI). We find that CPCs express Glut1 and that their rate of glucose utilization increases in the presence of high extracellular glucose, independently of insulin. Moreover, CPCs isolated from diabetic mice exhibit a marked and sustained increase in aerobic glycolysis, accompanied by an elevated level of 6-phophofructo-2-kinase/fructose-2,6- bisphosphatase 3—a phosphofructokinase 2 isoform known to sustain high rates of glycolysis. Our studies also show that increased glycolytic activity in diabetic CPCs is associated with lower glucose-derived carbon flux through the pentose phosphate and hexosamine biosynthetic pathways, but higher flux through the glycerolipid biosynthetic pathway. These results indicate that high rates of glycolysis in CPCs alter the activity of ancillary pathways of glucose metabolism, which are important for biosynthetic reactions, maintaining redox balance, and for resistance to stress. That such changes in glucose metabolism affect CPC function is indicated by our observation that increasing glycolysis at the PFK step is sufficient to decrease CPC proliferation in vitro. Informed by these observations, we suspect that diabetic dysfunction in CPCs is, at least in part, caused by a dysregulation of glucose metabolism and that correcting this metabolic defect will be a viable approach to optimize cell therapy for the diabetic heart. We propose to test the hypothesis that diabetes leads to an increase in the glycolytic activity in CPCs, which diminishes flux through key ancillary pathways of glucose metabolism. This metabolic dysregulation decreases CPC proliferation, survival, and secretory activity, and impairs the capacity of CPCs to promote myocardial repair. To test this hypothesis, we will: (1) examine how diabetes affects CPC competence and therapy; (2) elucidate the role of glucose metabolism in mediating CPC dysfunction in diabetes; and (3) determine whether rescuing defects in glucose metabolism improves cell therapy in the diabetic heart. Successful completion of the project will provide new understanding of the metabolic pathways that regulate stem/progenitor cell function and how they affect the outcomes of cell therapy for heart failure. These findings would facilitate the optimization of cell therapy protocols and inform ongoing and future cell therapy trials for the treatment of heart failure in both nondiabetic and diabetic patients.