Abstract 12587: Telomere Length Regulates Cellular Fate of Cardiac Progenitor Cells

Abstract

Myocardial regeneration following injury is severely limited by aging. Understanding the impact of age-associated factors such as telomere shortening is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs), which are currently used in clinical trials. Telomere length (TL) determines the proliferation potential such that short telomeres cause senescence of CPCs, however the impact of TL on regulating the balance between quiescence and differentiation of adult stem cells remains undetermined. We hypothesize that TL regulates the equilibrium between quiescence, proliferation, commitment and senescence, thus determining cellular fate of CPCs. CPCs were isolated from 3 mouse strains with varying TLs- common laboratory mouse strains FVB (TL:70Kb) and C57 (TL:50Kb), as well as a naturally occurring wild mouse strain, Mus musculus castaneus (CAST) possessing critically short telomeres (TL:18Kb) comparable to humans (TL:5-10Kb). CAST CPCs with short TLs have slower proliferation rate (-80% vs FVB, p<0.01), increased population doubling time and exhibit characteristics of senescence such as flattened cell morphology, increased beta-galactosidase activity (p<0.05) and p53 expression (1.7 fold, p<0.05). Interestingly, CAST CPCs also undergo basal differentiation in the absence of commitment cues, as evidenced by increased expression of lineage markers smooth muscle actin (SMA; 16.6 fold, p<0.01), Tie2 (1.7 fold, p<0.05), and sarcomeric actinin (1.75 fold). Acquisition of differentiation and senescence is accompanied by reduced expression of quiescence marker p21 (-33%). Consistent findings of senescence, increased basal differentiation (11.3 and 1.6 fold increase in SMA and Tie2 levels) and loss of quiescence (-26% decrease in p21 levels) are evidenced in CPCs isolated from old FVB mice with short TLs relative to young CPCs. Corroborative findings in adult human failing heart CPCs with short TLs suggests that telomere shortening tips the equilibrium away from quiescence and proliferation into differentiation and senescence leading to exhaustion of CPCs. Understanding mechanistically how TL regulates CPC fate will enable identification of molecular strategies to enhance the therapeutic effects of CPCs.