Abstract 17847: p53 Activity Controls Growth and Survival of Cardiac Stem Cells
The transcription factor p53 regulates a wide range of biological responses, which include DNA damage/repair, proliferation, apoptosis, and senescence. In the current work, we raised the possibility that p53 activity controls fate specification in cardiac stem cells (CSCs). To test this hypothesis, CSCs were isolated from the heart of WT and superp53 (Sp53) mice, which are characterized by an increased gene dosage of p53. At baseline, Sp53 CSCs exhibited a 30% shorter population doubling time and a 2-fold increase in Ki-67 labeling, indicating that enhanced p53 activity was unexpectedly coupled with higher proliferative potential. Consistently, the fraction of Sp53 CSCs expressing the cell cycle inhibitor p21Cip1 was 2-fold smaller and the frequency of γH2A.X foci, which reflect sites of DNA damage, was 2.6-fold lower. Also, the rate of apoptosis was 1.3-fold higher and the senescence-associated protein p16INK4a was undetectable in Sp53 CSCs. After exposure to doxorubicin (doxo), WT and Sp53 CSCs exhibited a differential pattern of expression of p53-target genes. In WT CSCs, the pro-apoptotic proteins Noxa and PUMA were upregulated 10-fold and 3-fold, respectively. Doxo treatment did not affect Noxa and PUMA in Sp53 CSCs, which showed a 5-fold increase in the nuclear localization of p21Cip1. Stress mediated by doxo promoted apoptosis in WT CSCs but induced cell cycle arrest in Sp53 CSCs, which exhibited a 5-fold more exuberant activation of the DNA damage repair response, as documented by the frequency of γH2A.X foci. Seventy-two hours following the removal of doxo, proliferation was largely restored in Sp53 CSCs, which displayed a level of Ki-67 labeling similar to baseline. In contrast, cell proliferation was significantly lower in WT CSCs, which showed a 3-fold higher level of expression of p16INK4a. These findings indicate that augmented p53 activity protects CSCs from stress-induced senescence in vitro. In vivo, apoptotic and cycling myocytes were significantly more frequent in Sp53 mice, documenting a higher level of cell turnover and the formation of a younger myocyte progeny in these animals. In conclusion, the level and activity of p53 affects the efficiency of DNA repair in CSCs, favoring cell cycle progression and survival and opposing senescence.
- © 2013 by American Heart Association, Inc.