Abstract 12195: Stem Cell Factor Activates Hypoxic Cardiac Stem Cells Improving Myocardial Aging
Low O2 tension favors hematopoietic stem cell quiescence while normoxia is required for their activation. Cardiac stem cell (CSC) function may be similarly regulated and disruption of the balance between hypoxic and normoxic CSCs may occur with aging. Here we report that the fraction of hypoxic CSCs increased 1.5-fold in the mouse heart from 3 to 30 months of age. In young and old mice, hypoxic CSCs were quiescent and lineage negative while cycling and early committed cells were restricted to the normoxic pool. At 3 months, hypoxic CSCs carried significantly longer telomeres than normoxic CSCs. Telomere length did not decrease with age in hypoxic CSCs, while a 43% shortening occurred in normoxic CSCs, which showed higher levels of p16INK4a expression. The quiescent state of the larger compartment of CSCs with long telomeres in the senescent heart imposes a great growth demand on normoxic CSCs, which generate a myocyte progeny that is chronologically young, but phenotypically old. To determine whether hypoxic CSCs can be activated to generate mechanically efficient myocytes and rejuvenate the aged heart, stem cell factor (SCF) was delivered to the LV of old mice. At 6 hours, hypoxic CSCs decreased 55% and normoxic CSCs increased 97%. At 2 days, SCF resulted in a 95% increase in the fraction of BrdU-labeled CSCs which led at 3 weeks to a 32% increase in CSC number. In SCF-treated mice, the fraction of BrdU-positive myocytes increased 114%; telomere length in these newly-formed myocytes was 75% longer than in BrdU-negative cells, indicating that regenerated myocytes derived from activation of CSCs with a younger cell phenotype. SCF decreased LV diastolic and systolic volumes and increased LV wall thickness. Diastolic and systolic wall stress decreased by 56% and 45% in treated mice, in which LV mass-to-chamber volume ratio increased 84% in diastole and 2.2-fold in systole. The expansion in LV mass was characterized by a 2.1-fold increase in the number of mononucleated myocytes. Conversely, binucleated myocytes decreased 12% in SCF-treated hearts. Thus, the compartment of quiescent, young CSCs can be stimulated in situ by SCF; this intervention repopulates the senescent heart with chronologically younger CSCs and myocytes, reversing the cardiac senescent phenotype in vivo.
- © 2013 by American Heart Association, Inc.