Abstract 16895: Senescent Cardiomyocytes Modulate the Function of Cardiac Stem Cells in the Niches of the Old Heart
Cardiac stem cells (CSCs) are clustered in niches and are connected by junctional proteins to myocytes, which act as supporting cells. The objective of this study was to determine whether cardiac aging is characterized by the formation of dysfunctional niches and whether young and senescent myocytes affect differently CSC fate. Forty and 20 cardiac niches were examined in young and old Fischer 344 rats, respectively. Although a single stem cell can be considered a niche, only clusters composed of two or more lineage negative CSCs were included in the analysis. From 4 to 28 months of age, the number of CSCs per niche increased 1.7-fold and the fraction of CSCs positive for the senescence-associated marker p16INK4a increased 14-fold. Apoptosis of CSCs increased with age and was restricted to p16INK4a-positive-cells. However, the process of clearance of senescent CSCs was inefficient: the fraction of p16INK4a-positive CSCs undergoing apoptosis decreased 3.5-fold with age, resulting in accumulation of senescent cells within the niche. In an attempt to compensate for the higher myocyte loss occurring in aged hearts, p16INK4a-negative CSCs proliferated 4-fold more in old than in young rats, experiencing progressive telomeric shortening. To define whether young and old myocytes influence differently proliferation and apoptosis of CSCs, myocytes and CSCs were co-cultured for 3 days. With respect to CSCs plated alone, old myocytes enhanced 2.2-fold BrdU incorporation in co-cultured CSCs. This effect was less apparent with young myocytes. No significant differences in CSC apoptosis were seen. Comparable results were obtained when CSCs and myocytes were plated in Transwell systems. Importantly, old myocytes released more IGF-1 than young myocytes; blockade of IGF-1 receptor in CSCs attenuated significantly the positive impact of myocytes on CSC replication. Collectively, our findings indicate that old CSCs accumulate in the niches of the aged heart and that senescent myocytes promote activation of p16INK4a-negative CSCs, which undergo repeated divisions and telomeric loss, generating an old progeny. Abnormal niche turnover limits the regenerative ability of the heart contributing to the manifestations of the aging cardiomyopathy.
- © 2012 by American Heart Association, Inc.