Abstract 704: Cardiac Progenitor Cell Aging Is Responsible for Organ Aging

Abstract

To establish whether the aging cardiomyopathy is dictated by depletion of the cardiac progenitor cell (CPC) pool and accumulation of old myocytes, we measured first the number of CPCs in rats at 4, 12, 20 and 28 months of age. CPCs are lineage-negative cells that express the stem cell antigens c-kit, MDR-1 and/or Sca-1. Unexpectedly, from 4 to 28 months, the number of CPCs in the heart increased ~3-fold. The increase in mitotic index of CPCs in the old heart indicated enhanced activation of CPCs which resulted in an increased number of myocyte progenitors and precursors and ultimately differentiated cardiomyocytes. These observations were at variance with the concomitant accumulation of p16 INK4a -positive-myocytes and the 6-fold increased rate of myocyte apoptosis in the senescent heart pointing to defects in the CPC compartment with aging. Activation and differentiation of old CPCs may generate a myocyte progeny that rapidly reaches senescence. To evaluate the biological age of CPCs, we measured two parameters of cellular aging: the senescence-associated protein p16 INK4a and telomere length. From 4 to 28 month, p16 INK4a -positive-CPCs increased from ~6% to ~81% resulting in a sharp decrease in the number of functionally-competent CPCs. Telomere length was measured by Q-FISH in cytospin preparations of c-kit-positive-cells collected from hearts at 3 and 27 months. In old hearts, the distribution of telomere length in CPCs, myocyte progenitors-precursors and developing myocytes was shifted to the left towards shorter telomeres. Average telomere length in old CPCs, myocyte progenitors-precursors and developing myocytes was 30%, 38% and 52% shorter than in the corresponding young cell populations, respectively. Importantly, 55% of old CPCs and 15% of young CPCs had telomeres less than 8 kbp and were p16 INK4a -positive. Thus, telomere attrition in CPCs with age leads to the generation of a myocyte progeny that rapidly acquires the senescent phenotype. However, nearly 16% of the old CPC pool had telomeres greater than 14 kbp pointing to a relevant growth reserve of the senescent myocardium. In conclusion, CPC aging with reduction in telomeric length dictates the formation of a senescent progeny which conditions organ aging and failure.