Abstract 256: Dysfunctional Cardiac Stem Cell Niches Condition the Aging of the Heart

Abstract

The objective of this study was to determine whether aging of the heart is characterized by alterations in the cellular composition of cardiac niches and defective cardiomyogenesis. By employing a morphometric approach in which the three-dimensional structure of each niche was evaluated, we examined 40 and 20 cardiac niches in young and old Fischer 344 rats, respectively. Although a niche can include a single stem cell, clusters composed of three or more cardiac stem cells (CSCs) and early lineage committed cells (LCCs) were included in the analysis. LCCs expressed the stem cell antigen c-kit in combination with the marker of cardiac commitment GATA4. The average volume of the niches did not vary with age. Surprisingly, the number of lineage-negative CSCs increased from 4 to 28 months. Young niches contained 6 CSCs while old niches showed 10 CSCs. However, the fraction of CSCs positive for the senescence-associated marker p16 INK4a increased 14-fold with age, from 6% to 85%. Corresponding values for LCCs were 8% and 82%. Apoptosis of CSCs-LCCs increased with age and was restricted to p16 INK4a -positive-cells. However, the fraction of senescent CSCs-LCCs undergoing apoptosis decreased 3.5-fold with age: apoptosis was detected in 7% and 2% of p16 INK4a positive CSCs-LCCs of young and old animals, respectively resulting in the accumulation of senescent cells.Freshly isolated CSCs proliferated in response to growth stimuli but this effect was attenuated in old cells. This finding was consistent with the decreased expression of the insulin-like growth factor receptor 1 (IGF-1R) in senescent CSCs. Collectively, the accumulation of senescent CSCs and the poor response of p16 INK4a- negative CSCs to growth stimuli determined the formation of dysfunctional niches. Abnormal niche turnover led to the generation of rapidly aging cardiomyocytes. In conclusion, the cellular composition of the niches varies with age. The decrease in the number of functionally-competent CSCs-LCCs together with the accumulation of senescent CSCs-LCCs limits the ability of CSC niches to repopulate the senescent ventricular myocardium.