Oxygen cycling to improve survival of stem cells for myocardial repair: A review

Heart disease represents the leading cause of death among Americans. There is currently no clinical treatment to regenerate viable myocardium following myocardial infarction, and patients may suffer progressive deterioration and decreased myocardial function from the effects of remodeling of the necrotic myocardium. New therapeutic strategies hold promise for patients who suffer from ischemic heart disease by directly addressing the restoration of functional myocardium following death of cardiomyocytes. Therapeutic stem cell transplantation has shown modest benefit in clinical human trials with decreased fibrosis and increased functional myocardium. Moreover, autologous transplantation holds the potential to implement these therapies while avoiding the immunomodulation concerns of heart transplantation. Despite these benefits, stem cell therapy has been characterized by poor survival and low engraftment of injected stem cells. The hypoxic tissue environment of the ischemic/infracting myocardium impedes stem cell survival and engraftment in myocardial tissue.Hypoxic preconditioning has been suggested as a viable strategy to increase hypoxic tolerance of stem cells. A number of in vivo and in vitro studies have demonstrated improved stem cell viability by altering stem cell secretion of protein signals and up-regulation of numerous paracrine signaling pathways that affect inflammatory, survival, and angiogenic signaling pathways. This review will discuss both the mechanisms of hypoxic preconditioning as well as the effects of hypoxic preconditioning in different cell and animal models, examining the pitfalls in current research and the next steps into potentially implementing this methodology in clinical research trials.