Abstract 15932: Telomere Length and Autophagy Modulate Cardiac Progenitor Cell Fate
Several cell intrinsic changes occurring with age lead to exhaustion of the stem cell pool. Delineating the role of age-associated factors such as telomere shortening is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesize that telomere length (TL) determines cellular fate by regulating autophagy and maintaining the homeostatic equilibrium of CPCs. CPCs were isolated from 3 mouse strains with varying TLs - common laboratory strains FVB (TL:70Kb) and C57 (TL:50Kb), as well as a naturally occurring wild strain, Mus musculus castaneus (CAST) possessing 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) coinciding with senescence as identified by increased beta-galactosidase activity (p<0.05) and p53 and p27 expression (1.7 and 5.4 fold respectively). Interestingly, CAST CPCs also undergo basal differentiation in the absence of commitment cues, 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 (s-actinin,1.75 fold). Acquisition of differentiation and senescence is accompanied by reduced expression of quiescence markers p21 and p57 (-33% and -60% respectively) that coincides with increased autophagy, a catabolic protein degradation process known to maintain stem cell homeostasis. Autophagy flux is increased in CAST CPCs as evidenced by increase in LC3 (1.5 fold) and reduction in p62 levels (-52%, p<0.05). p62 expression further decreases in CAST CPCs treated with Dexamethasone, a non-specific inducer of CPC differentiation (-61% vs control CAST CPCs). Inhibition of autophagosome formation, but not autolyosome formation decreases the expression of basal commitment and senescence markers in CAST CPCs. Overall the data suggests that short telomeres activate autophagy to accommodate cell fate changes that tips the equilibrium away from quiescence and proliferation into differentiation and senescence, leading to exhaustion of CPCs. Understanding mechanistically how TL regulates autophagy and CPC fate will enable identification of molecular strategies to enhance the therapeutic effects of CPCs.
Author Disclosures: C. Matsumoto: None. J. Emathinger: None. P. Quijada: None. A.B. Levinson: None. M. Shin: None. N. Nguyen: None. M. Sussman: None. N. Hariharan: None.
- © 2016 by American Heart Association, Inc.