RATIONALE: Age and coronary artery disease may negatively affect the function of 
human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for 
autologous cell transplantation in the failing heart.
OBJECTIVE: Insulin-like growth factor (IGF)-1, IGF-2, and angiotensin II (Ang 
II), as well as their receptors, IGF-1R, IGF-2R, and AT1R, were characterized in 
c-kit(+) hCSCs to establish whether these systems would allow us to separate 
hCSC classes with different growth reserve in the aging and diseased myocardium.
METHODS AND RESULTS: C-kit(+) hCSCs were collected from myocardial samples 
obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac 
surgery for coronary artery disease. The expression of IGF-1R in hCSCs 
recognized a young cell phenotype defined by long telomeres, high telomerase 
activity, enhanced cell proliferation, and attenuated apoptosis. In addition to 
IGF-1, IGF-1R(+) hCSCs secreted IGF-2 that promoted myocyte differentiation. 
Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, 
identified senescent hCSCs with impaired growth reserve and increased 
susceptibility to apoptosis. The ability of IGF-1R(+) hCSCs to regenerate 
infarcted myocardium was then compared with that of unselected c-kit(+) hCSCs. 
IGF-1R(+) hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of 
IGF-1R(+) hCSCs with IGF-2 resulted in the formation of more mature myocytes and 
superior recovery of ventricular structure.
CONCLUSIONS: hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which 
are potent modulators of stem cell replication, commitment to the myocyte 
lineage, and myocyte differentiation, which points to this hCSC subset as the 
ideal candidate cell for the management of human heart failure.