We have demonstrated that human neonatal cardiosphere derived cells (CDCs) derived from the young are more regenerative due to their robust secretome. However, it is unclear how the decompensated pediatric heart impacts the functional activity of their CDCs. Our aim was to characterize the potency of pediatric CDCs derived from normal functioning myocardium of control heart disease (CHD) patients to those generated from age matched end stage heart failure (ESHF) patients and determine the mechanisms involved. ESHF derived CDCs contained a higher number of c-kit+, Islet-1+, and Sca-1+ cells. When transplanted into an infarcted rodent model, ESHF derived CDCs significantly demonstrated higher restoration of ventricular function, prevented adverse remodeling, and enhanced angiogenesis when compared to CHD patients. The superior functional recovery of the ESHF derived CDCs was mediated in part by increased SDF-1α and VEGF-A secretion resulting in augmented recruitment of endogenous stem cells and proliferation of cardiomyocytes. We determined the mechanism is due to the secretome directed by the heat shock response (HSR), which is supported by three lines of evidence. Firstly, gain of function studies demonstrated that increased HSR induced the lower functioning CHD derived CDCs to significantly restore myocardial function. Secondly, loss-of function studies targeting the HSR impaired the ability of the ESHF derived CDCs to functionally recover the injured myocardium. Finally, the native ESHF myocardium had an increased number of c-kit+ CSCs. These findings suggest that the HSR enhances the functional activity of ESHF derived CDCs by increasing their secretome activity, notably SDF-1α and VEGF-A.

Sudhish Sharma1, Rachana Mishra1, David Simpson1, Brody Wehman1, Evan J. Colletti2, Savitha Deshmukh1, Srinivasa Raju Datla1, Keerti Balachandran1, Yin Guo1, Ling Chen1, Osama T. Siddiqui1, Shalesh Kaushal3, and Sunjay Kaushal11Division of Cardiac Surgery, University of Maryland School of Medicine 110 S. Paca Street, 7th floor Baltimore, Maryland 21201, USA2Department of Animal Biotechnology, University of Nevada, Reno, Nevada, 89557, USA3Retina Specialty Institute, 6717 North 11thPlace Suite C, Gainesville, Florida 32605 USA

Published in final edited form as:Stem Cells. 2015 April ; 33(4): 1213–1229. doi:10.1002/stem.1937.