Abstract 16758: Cardiosphere Derived Cells From Pediatric End-Stage Heart Failure Patients Have Enhanced Functional Activity Due to the Heat Shock Response Regulating the Secretome
Rationale: Results from pre-clinical studies and a Phase I clinical study demonstrates promising functional recovery by adult cardiosphere derived cells (CDCs) to repair damaged myocardium. We have previously demonstrated that age regulates the functional recovery of neonatal CDCs due to their more effective secretome. However, how advanced failure pediatric hearts regulate their derived CDC’s functional activity is still unknown.
Objective: Our aim was to compare the functional potency between pediatric CDCs derived from normal myocardium of congenital heart disease (CHD) patients and from dysfunctional myocardium of pediatric end stage failing heart (ESHF) patients and determine the mechanisms involved.
Methods and Results: ESHF derived hCDCs had a higher number of cardiac stem cells expressing c-kit+, Islet-1+, and Sca-1+. When transplanted in an infracted rodent model, ESHF derived hCDCs had a significantly higher preservation of ventricular function, prevented adverse remodeling, and enhanced angiogenesis when compared with CHD derived CDCs. The superior functional recovery of the ESHF derived hCDCs was mediated in part by increased SDF-1α and VEGF-A secretion which recruited more endogenous stem cells and proliferation of cardiomyocytes. The mechanism for the superior secretome is due to the heat shock response (HSR) which is 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 to the same extent as ESHF derived CDCs. Secondly, loss-of function studies targeting the HSR down regulated the ability of the ESHF derived CDCs to functionally recover the injured myocardium. Finally, the HSR alone increased the number of the c-kit+ CSCs both in vitro and in vivo.
Conclusion: These findings suggest that the HSR enhances the functional activity of ESHF derived CDCs by regulating their secretome.
Author Disclosures: S. Sharma: None. R. MIshra: None. D. Simpson: None. E.J. Colletti: None. S. Deshmukh: None. L. Chen: None. B.P. Wehman: None. S. Kaushal: None. S. Kaushal: None.
- © 2014 by American Heart Association, Inc.