Abstract 12660: Both Insulin-Like Growth Factor-1 and -2 Receptor Control Human Cardiac Progenitor Cells Proliferation and Differentiation in Children With Congenital Heart Malformation
Background- Myocyte self-renewal is hindered by the decline of intrinsic regenerative potential due to substantial changes in cardiac progenitor pool during aging process. Although previous studies have shown the genes responsible for myocardial aging in mice, the molecular mechanisms involved in postnatal growth and adaptation in children remains to be elucidated.
Methods- Myocardial tissue specimens were obtained from 60 patients during surgical repair between the ages of 0 and 6. Individual human cardiac progenitor cells (CPCs) were isolated and classified into 2 groups, neonatal and infant CPCs, along with age at surgery. Cell proliferation, angiogenic potential, and global gene expression analysis were examined. To determine whether human CPCs harbor the biological defects of telomere maintenance and telomerase catalytic activity with age, nuclear flow fluorescent in situ hybridization and telomere amplification protocol were performed.
Results- Neonatal CPCs showed a higher replicative capacity that declined with age but correlated inversely with senescence associated beta-galactosides activity. Telomere shortenings were obvious, whereas levels of telomerase activity did not change in infant CPCs compared with neonatal CPCs. Because increased proliferation could not account for the phenotype of neonatal CPCs, we further examined whether aging may affect human CPC function. Tube formation analysis showed that infant CPCs had higher angiogenic potential with the secretion of various growth factors including hepatocyte growth factor, whereas insulin-like growth factor (IGF) -1 and -2 receptor showed a higher expression in neonates when myocyte turnover was prominent. Microarray analysis revealed that genes, including heparin-binding EGF-like growth factor which promote cardiomyocyte proliferation, were more expressed in neonatal CPCs.
Conclusions- Collectively, intrinsic human CPCs express genes essential for myocytes formation and maturation in postnatal stage to maintain the myocyte numbers by supplying local vasculature and secreting paracrine effectors. Both IGF-1 and -2 receptor may be a therapeutic target to modulate human CPC replication and differentiation in the development of new therapies for heart failure.
- © 2011 by American Heart Association, Inc.