Abstract 16: Cardiosphere Derived Cells from Pediatric End-Stage Heart Failure Patients Have Enhanced Functional Activity Due to the Heat Shock Response

Abstract

Background: The potential of novel cell based therapies using cardiosphere derived cells (CDCs) to replace or repair damaged cardiac tissue is an attractive therapy and Phase I clinical trials in adults report encouraging results. We have previously demonstrated that age plays an important role in controlling the functional activity of CDCs and now we will determine how the heart’s physiology may change the functional activity of pediatric end-stage heart failure (ESHF) derived CDCs when compared to age-match control derived CDCs. Methods and Results: Our results shows that ESFH derived CDCs have significantly increased numbers of CSCs, including c-kit+, ISL-1+ and Sca-1+ cells. They are functionally more potent in an infarcted rodent model as compared to hCDCs derived from congenital heart disease (CHD) age-matched controls which have normal myocardium. The functional recovery was mediated in part by increased secretion of cytokines, SDF-1α and VEGF-A, which stimulated more angiogenesis, recruitment of endogenous stem cells, and proliferation of cardiomyocytes. The possible mechanism for this increased cytokine secretion was due to the activation of heat shock response (HSR), supported by three lines of evidence. First, gain of function studies demonstrated that the HSR induced the low functioning CHD-derived CDCs to significantly recover the injured myocardium, even more than the ESHF-derived CDCs by increasing cytokine secretion. Secondly, loss-of function studies targeting the HSR down regulating the ability of the ESHF-derived CDCs to secrete cytokines and thus functionally recover the injured myocardium. Finally, the HSR alone increased the number of the endogenous cardiac stem cell population and recovered the injured myocardium. We will present the results showing that activation of HSR expands cardiac stem cells (CSCs) without losing their phenotypic characteristics. Conclusion: Collectively, the present work demonstrates a novel biological activity of the HSR in its ability to increase the number of functional CSCs while maintaining the ‘stemness’ of these cells that have direct implications for future clinical trials.