Cardiosphere-derived cells from pediatric end-stage heart failure patients have enhanced functional activity due to the heat shock response regulating the secretome.
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 to 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 with 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. First, gain of function studies demonstrated that increased HSR induced the lower functioning CHD-derived CDCs to significantly restore myocardial function. Second, 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(+) cardiac stem cells. 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.
Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Sudhish
S
Sharma
Rachana
R
Mishra
David
D
Simpson
Brody
B
Wehman
Evan J
EJ
Colletti
Savitha
S
Deshmukh
Srinivasa Raju
SR
Datla
Keerti
K
Balachandran
Yin
Y
Guo
Ling
L
Chen
Osama T
OT
Siddiqui
Shalesh
S
Kaushal
Sunjay
S
Kaushal
D000818:Animals; D006333:Heart Failure / Q000473:pathology*; D018869:Heat-Shock Response / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D013234:Stem Cells / Q000502:physiology*
Adult stem cells; Cardiac stem cell transplantation; Heart failure; Heat stress; Myocardial ischemia; Pediatrics; Tissue-specific stem cells