Abstract 16912: Cardiac Stem Cell Function is Regulated by Hypoxic and Normoxic Niches within the Myocardium
In the heart, cardiac stem cells (CSCs) are nested in niches. The objective of this work was to establish whether hypoxic and normoxic niches coexist in the heart and whether their relative proportion changes with aging. Hypoxic and normoxic niches were found in young and old mice, but the number of hypoxic CSCs increased ∼5-fold with aging. The role of O2 in CSC function was determined by FACS in isolated cells. At 3 and 30 months, hypoxic CSCs were quiescent and lineage negative while cycling and early committed cells were restricted to the normoxic pool. By pulse-chase assay, long-term label-retaining CSCs had low O2 content indicating that hypoxic CSCs correspond to rarely dividing highly undifferentiated stem cells. To test the possibility that loss of hypoxic CSCs is replenished by activation of normoxic CSCs, mice were treated with tirapazamine, a drug that kills only hypoxic cells. This intervention led in young mice to a 50% decrease in the CSC pool, which was composed exclusively of normoxic cells. Over a 12 day-period, however, the number and the proportion of hypoxic and normoxic CSCs were restored. This compensatory response, which involved symmetric division of normoxic CSCs with formation of two daughter stem cells, was lost with aging. Importantly, telomeres were longer in hypoxic than normoxic CSCs and this difference was more apparent in old mice. Telomere length did not change with age in hypoxic CSCs but decreased 40% in normoxic CSCs. Consistently, the senescence-associated protein p16INK4a was detected only in normoxic CSCs. By echo-Doppler, MRI, and invasive hemodynamics, ventricular dilation and depressed cardiac performance in old mice were characterized by alterations in diastolic and systolic indices of contractility. Additionally, old myocytes showed prolonged action potential, and a marked reduction in Ca2+ transients and sarcomere shortening. In conclusion, myocardial aging is characterized by a decrease in the pool of actively cycling CSCs. The quiescent state of the larger compartment of hypoxic CSCs with long telomeres is coupled with intense growth of normoxic CSCs, which generate functionally defective old myocytes with short telomeres, conditioning the loss of structural and functional integrity of the senescent heart.
- © 2012 by American Heart Association, Inc.